Number of reported cases where viruses were used to treat deadly Mycobacterium infections have just increased by a factor of five. In a new study, a team led by researchers from the University of Pittsburgh and the University of California at San Diego reports 20 new case studies on the use of the experimental treatment, demonstrating the success of the therapy in more than half of patients. .
It is the largest series of case studies ever published for therapy with bactericidal viruses known as bacteriophages, providing unprecedented detail on their use to treat serious infections while laying the groundwork for a future clinical trial.
Some of these are spectacular results, others are complicated. But if we do 20 cases, it becomes much more compelling that the phages contribute to favorable outcomes -; and in patients who have no other alternatives.”
Graham Hatfull, the Eberly Family Professor of Biotechnology at the Kenneth P. Dietrich School of Arts and Sciences at the University of Pittsburgh
Each patient treated in the study was infected with one or more strains of Mycobacterium, a group of bacteria that can cause deadly, treatment-resistant infections in people with compromised immune systems or with the lung disease cystic fibrosis. In 2019, Hatfull led a team that demonstrated the first successful use of phages to treat one of these infections.
“For clinicians, these are a real nightmare. They’re not as common as some other types of infections, but they’re among the most difficult to treat with antibiotics,” Hatfull said. “And especially if you take these antibiotics for long periods of time, they’re either toxic or not very well tolerated.”
Last month, researchers from the University of Pittsburgh were involved in two new case studies that successfully treated patients in collaboration with colleagues from National Jewish Health and Harvard University. But those reports represent only a fraction of the things the team has been involved in behind the scenes. Since 2019, Hatfull and his lab have handled requests from more than 200 clinicians seeking treatments for their patients, working with them to find phages that could be effective against the specific strain of bacteria infecting each patient.
The latest article, published today in the magazine Clinical infectious diseases together with collaborators from 20 institutions, the amount of published data on the effectiveness of the therapy is scaling up drastically.
“These are incredibly brave doctors jumping off the ledge to do an experimental therapy to help patients who have no other options,” Hatfull said. “And each of these collaborations represents a marker that can move the field forward.”
Looking at measurements of patient health and whether patient samples still showed signs of Mycobacterium infections, the team found that the therapy was successful in 11 out of 20 cases. None of the patients showed any side effects to the treatment.
In another five patients, the results of the therapy were inconclusive, and four patients showed no improvement. According to Hatfull, even these apparent failures are key to making the therapy available to more patients. “In some ways, those are the most interesting cases,” he said. “Understanding why they didn’t work will be important.”
Several unexpected patterns emerged from the case studies. In 11 cases, researchers couldn’t find more than one type of phage that could kill the patient’s infection, although standard practice would be to inject a cocktail of several viruses so that the bacteria are less likely to develop resistance.
“If you had asked me three years ago if that was a good idea, I would have had a seizure,” Hatfull said. “But we just didn’t observe any resistance, and we didn’t see any treatment failure due to resistance, even when using just a single phage.”
In addition, the team saw that some patients’ immune systems attacked the viruses, but only in a few cases did their immune systems render the virus ineffective. And in some cases, despite such an immune response, the treatment was still successful. The study paints an encouraging picture for the therapy, Hatfull said, and one that opens up the possibility for new phage regimens that clinicians could use to maximize the chances of treatment success.
In addition to the study’s importance for patients dealing with Mycobacterium infections, it also represents a significant advance for the broader field of phage therapy. A concern in some quarters is that researchers may only publish case studies in which phage therapy is successful.
“A series of sequential case studies, where we’re not picking, is a much more transparent way to see what works and what doesn’t,” Hatfull says. “This adds significant weight to the feeling that the therapy is safe.”
The lab continues to provide phages for more patients -; while simultaneously doing research to widen the funnel that narrowed an initial group of 200 patients to 20, in hopes of treating more people without other options.
“We haven’t figured out how to find or develop phages that can get any strain of bacteria in these patients,” Hatfull said. “That’s one of the big challenges ahead of us.”
Dirk, R. M., et al. (2022) Phage therapy of mycobacterial infections: compassionate use of phages in twenty patients with drug-resistant mycobacterial disease. Clinical infectious diseases. doi.org/10.1093/cid/ciac453†
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