Managing phage therapy to help save lives

Written by Paul Schattenberg

Scientists from the Texas A&M College of Agriculture and Life Sciences were among those who provided the biochemical tools needed to help save a man’s life in a unique emergency response in 2016.

Study contributors from the Texas A&M University Center for Phage Technology, left to right: James Clark, research specialist; Tram Le, coordinator of the technical laboratory; Mei Liu, Ph.D., program director; and Jason Gill, Ph.D., professor and associate director. Absent from the photo, Adriana Hernandez-Morales and Ryland Young, Ph.D., also contributed to the study. (Photo courtesy of the Center for Phage Technology.)

Now, these scientists at the Center for Phage Technology at the Texas A&M Department of Biochemistry and Biophysics, Bryan-College Station, have completed a study of this treatment as well as other possibilities for phage therapy.

Their study, “Comparative genomics of Acinetobacter baumannii and therapeutic bacteriophages from a patient undergoing phage therapy,” was recently published in the scientific journal Nature Communications.

The threat of antimicrobial resistance has become a global concern, with the World Health Organization estimating that at least 50 million people a year worldwide could die from it by 2050. Scientists from the Center for Phage Technology believe that therapeutic phages can be used to fight against these resistant bacterial infections.

The first case involved scientists from the phage center working in collaboration with other scientists and physicians from the University of California San Diego, UC San Diego, the School of Medicine and the Medical Research Center of the United States Navy – Biological Defense Research Directorate. Together they worked to identify the phages and determine a treatment plan for Tom Patterson, professor of psychiatry at UC San Diego School of Medicine, who was infected with a deadly pathogen while vacationing in Egypt.

About Phage

Bacteriophages, or phages, are viruses that can infect and kill bacteria without adversely affecting human or animal cells. Phages can be used alone or in combination with antibiotics or other drugs to treat bacterial infections.

“Bacteriophage therapy is an emerging field that many researchers believe may offer new ways to combat antimicrobial-resistant bacteria,” said Mei Liu, Ph.D., program director at the Center for Phage Technology and researcher principal of the study. “At the center, we are interested in the applications of phage therapeutics to combat multidrug-resistant bacterial infections.”

She said the center’s work is aided by the team’s deep knowledge of phage biology, particularly in the areas of phage lysis and phage genomics.

Patterson’s predicament

In 2015, while vacationing in Egypt over the Thanksgiving holiday, Patterson began experiencing severe abdominal pain, nausea, and vomiting. Local doctors diagnosed him with pancreatitis and treated him accordingly, but the treatments did not work and his condition worsened.

He was then flown to Germany, where doctors found fluid around his pancreas and took cultures from the contents of the fluid. Cultures showed he had been infected with a multidrug-resistant strain of Acinetobacter baumannii, an often deadly pathogen found in hospital settings and in the Middle East. The same pathogen has also been identified in many wounded US service members returning home from service in that part of the world.

In Germany, Patterson was treated with a combination of antibiotics and his condition improved to such an extent that he could be airlifted to the intensive care unit at Thornton Hospital in the University Health System. UC San Diego Health. There, however, the medical team discovered that the bacteria had become resistant to antibiotics.

Tom Patterson, in his hospital bed, received phage therapy from Robert “Chip” Schooley, MD, left, of UC San Diego Health. (Courtesy photo used with permission of Dr. Tom Patterson)

A “compassionate use” exemption for phage therapy was requested by Dr. Robert “Chip” Schooley, the UC San Diego physician treating Patterson. It received quick approval from the United States Food and Drug Administration, FDA, to continue.

Shortly after beginning phage treatment, Patterson awoke from a months-long coma. After a long recovery, his health improved greatly and he was able to return to life as it was before the infection.

Acinetobacter baumannii and other resistant pathogens

Acinetobacter baumannii is recognized as an important bacterial pathogen in nosocomial infections. A 2019 Centers for Disease Control and Prevention report said antibiotic-resistant pathogens cause more than 2.8 million infections and more than 35,000 deaths annually in the United States.

Several characteristics of the pathogen that infected Patterson impacted treatment regimens and outcomes, said Ry Young, Ph.D., director of the Center for Phage Technology.

Patterson’s wife, Steffanie Strathdee, Ph.D., associate dean of global health sciences at UC San Diego School of Medicine and an infectious disease epidemiologist, had reached out to Young asking for his help in finding a treatment. for her husband once she learned of Young’s disease. extensive work with phages.

Young and his lab team took on the challenge and worked almost nonstop for three months to help find a solution.

Phages are viruses that can infect and kill bacteria without affecting human or animal cells. Phage therapy was widely used in the early 20th century before the use of antibiotics. (Drawing)

“Cases of resistant infections are becoming more common and very few new antibiotics are available, so the use of bacteriophages to treat or control multidrug-resistant infections is being reconsidered as an alternative strategy,” Young said. “Phage therapy is actually a very old concept, having been widely used in the early 20th century in the pre-antibiotic era.”

Phage therapy has also been successful in several more recent case studies involving multidrug-resistant strains of P. aeruginosa, Staphylococcus aureus, and Escherichia coli.

“Phages had been discounted as a potential treatment for bacterial infections when antibiotics became widely used in the United States,” Liu said. “But in other parts of the world, especially where antibiotics were not immediately available, researchers and doctors continued to develop and practice phage therapy. We are now seeing more and more examples of how phage therapy can be used when antibiotics alone are not enough to treat bacterial infections.

Lessons from the Patterson case

Jason Gill, Ph.D., a professor in the Texas A&M Department of Animal Science and associate director of the Center for Phage Technology, said the Patterson case and similar case studies dealing with multidrug-resistant bacteria have been encouraging in terms of clinical outcomes, further investigation of the phage-host interaction during treatment and its implications is needed.

“The recent study showed that resistance to therapeutic phages emerged early and that acquisition of new mobile elements by bacteria may occur during treatment,” said Gill, corresponding author of the study. “It is important to have thorough genomic phage analysis prior to phage treatment to maximize treatment success and minimize both effort and resources. There is also a need for conventional experimental assays for the range of phage hosts and growth characteristics.

Gill also noted that using well-characterized phages in a phage cocktail can avoid redundancy and significantly save time and effort in phage production and purification. Eight of the nine phages used for the treatment in the Patterson case were found to be closely related, and this knowledge could have been used to streamline the process if the investigators had known this when assembling the treatment.

“The Patterson case has done much to increase awareness of phage therapy and its effectiveness as an alternative therapy for multidrug-resistant pathogen strains,” Liu said. “The success of phage therapy in this and other cases has brought greater attention to its use and effectiveness.”

Liu added that the Center for Phage Technology is focused on developing the technology, standardizing optimal delivery procedures, and obtaining the necessary approvals from regulatory agencies to make phage therapy available to patients in the United States. United.

“A lot of what we did in the Patterson case was unconventional because of the context of phage therapy at the time,” Liu said. “But there have been many advances in genomic sequencing and other technologies since then. Today, it would be a much faster and more efficient process to develop and implement phage therapy if there were another case similar to Patterson’s.

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