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Get the most interesting and important stories from the University of Pittsburgh.Research updates: Making progress on an ‘antibiotic nightmare’
Mycobacterium abscessus is among the deadliest bacteria in the world, earning the nickname “antibiotic nightmare” among clinicians. With millions of cases of antibiotic-resistant infections each year in the U.S. alone, developing alternate therapies is ever more important to keeping the clinician’s toolbox full.
A new paper from biologist Graham Hatfull, published today in Nature Medicine, advances the science behind bacteriophage therapy to help treat antibiotic resistant lung infections. While the case described in the paper did not result in a cure for the patient, it was an example of how researchers can learn from all circumstances to advance knowledge that will improve treatment for others.
Tuberculosis, too?
It’s not just M. abscessus infections: Graham Hatfull’s team is also investigating whether phages could help people with tuberculosis, which is becoming increasingly resistant to antibiotics and which kills more than 1.5 million people each year worldwide. In a March 2021 paper, Hatfull’s group proposed a five-phage cocktail that was effective in killing a broad spectrum of Mycobacterium tuberculosis strains.
“This case study certainly provides key insights into how best to use bacteriophages therapeutically,” said Hatfull, who is the Eberly Family Professor of Biotechnology and HHMI Professor at Pitt.
Hatfull’s lab has identified and sequenced the genes of thousands of phages—bacteria-killing viruses—to see which can integrate with bacterial DNA and interrupt its expression, effectively stopping infection. In 2019, he proved this kind of treatment can really work.
A British teenager with cystic fibrosis was ravaged by an infection of M. abscessus. While researching experimental treatment options, her mother learned about Hatfull’s lab and contacted him about giving phage treatment a try. The cocktail of intravenous and topical phages slowed the infection and saved her life.
Based on this success, Hatfull and his team earned international acclaim. When he presented the teen’s case at a 2019 seminar, it caught the attention of a pulmonologist at Johns Hopkins University, Keira A. Cohen, who had been caring for a man with a lung infection of M. abscessus. Could phages help this patient, too?
The new paper describes him as an older man with lung diseases stemming from two infections, M. abscessus and Mycobacterium avium complex. He wasn’t responding well to traditional multidrug therapy, and he was also having side effects from his prolonged use of antibiotics including hearing loss, balance problems and weight loss. His infection and quality of life were so bad that he was referred to palliative care.
Hoping for a dramatic turn, Cohen sent a sample of her patient’s mycobacterial species to the Hatfull Lab. It turned out that the man’s M. abscessus strain was susceptible to the same three phages used in the London patient. After getting approval from their local institutions and compassionate use permission from the Food and Drug Administration, they gave the treatment a shot.
Unlike the antibiotics, the patient didn’t have negative reactions to the therapy, which was delivered intravenously. However, he also didn’t have a sustained reaction like the London patient. During treatment, his bacterial levels dropped, but on prolonged phage administration, they rebounded. His immune system had waged a strong response against the phages.
The researchers posit that the key lies in the immune reaction. The London patient had had a double-lung transplant and was on immunosuppressing drugs at the time of her phage therapy. It’s possible, they theorize, that those drugs prevented or delayed her immune system’s response to the phages, which gave them time to neutralize the infection.
Even though the phage therapy didn’t provide lasting relief to this second patient, it still marks an important push forward in scientists’ search for treatments for drug-resistant lung infections.
First, they suspect that an aerosolized delivery, similar to an asthma inhaler, might be a good alternative to an injection to target disease in these types of patients. Cohen, who’s co-author on the new paper, is currently trying that approach on the elderly patient. Second, the authors suggest that using the phages sequentially rather than altogether, could help to stay one step ahead of the immune system. Lastly, future trials could potentially employ immunosuppressing drugs to confirm whether that indeed is the factor that helped the London patient’s therapy succeed.