Cystic Fibrosis Case

Overview of the Therapy Used

•  Isabelle Carnell-Holdaway, a 17-year old teenager, has cystic fibrosis, which is a result of her deteriorating respiratory condition following a heart transplant in 2017. However, experimental treatment based on bacteriophages helped save her life.
• While she initially took antibiotics, they failed to treat her condition, infecting her surgical wound, liver, and over 20 different parts on her skin. Carnell-Holdaway says that one doctor told her that she had less than 1% chance of survival.
• The same doctor, Helen Spencer, a respiratory pediatrician and lung transplant expert based at Great Ormond Street Hospital in London, recommended the family to a microbiologist consultant based in the U.S. called Graham Hatfull, who did his thesis on phage therapy.

What Was Done During the Therapy?

• Hatfull's team requested a sample of Carnell-Holdaway's bacteria and developed a combination of three viruses designed to eliminate Mycobacterium abscessusIsa specifically, the bacteria causing Carnell-Holdaway's infection.
• Hatfull's team examined a collection of approximately 10,000 phages and narrowed it down to 50 – 100 phages, then finally selected only one phage virus capable of effectively infecting and eliminating the bacteria.
• The team also found two other phage viruses, but they were weak at killing the bacteria. The team decided to genetically modify the weak viruses and turned them into "really good killers," according to Hatfull.
• Spencer notes that when Carnell-Holdaway returned home, she was "not eating, had severe weight loss, had an abnormal liver function, and skin nodules were popping up — one or two every week." She stayed in bed for months and was very weak, her mother says.

Metrics of Success

• After two months, Carnell-Holdaway received her first dose of phage therapy, and a "big lesion by her liver disappeared." Along with the bacteriophage treatment, she also took IV (intravenous — through the vein) antibiotics.
• Within weeks, her appetite improved, and she started gaining weight. Likewise, the wounds on her skin were also gradually healing.
• Carnell-Holdaway returned to school and started attending classes daily, the first time in her life, without any issue at all.
•  Eleven months later, her skin was still causing lesions, but infrequently, and Spencer believed that Carnell-Holdaway's treatment was long term and not a short fix.

Poly-microbial Bone Infection Case

Overview of the Therapy Used

• A 42-year man had an accident and was admitted to Hadassah-Hebrew University Medical Center. The patient had severe leg fractures and was treated and discharged.
•  Nine days later, an infection was detected on the leg. Again, six weeks later, another infection was detected despite having undergone prolonged antibiotic treatment for six weeks. The man had developed resistance to "Acinetobacter baumannii (Ab) and Klebsiella pneumoniae (Kp) infections."
• The wound refused to respond to the antibiotics administered to the patients. Seven months into the treatment, the doctors recommended a knee amputation, but the patient refused. He resorted to phage therapy as a last resort.

What Was Done During the Therapy?

•  Two types of phage viruses were administered to target both the Ab and Kp infections.
• The therapy involved administering "1 ml of each phage" virus for over 35 minutes.
• The first three doses were administered while the patient was in the intensive care unit to help monitor any adverse changes.
• Luckily, no adverse changes were experienced, following the 5-day treatment process.

Metrics of Success

• The first signs of healing were noticed during the first therapy, including the elimination of chronic bone pain.
• During the first week of treatment, Ab was completely eradicated from the healing wound. A second phage therapy was then administered for six more days one week later.
•  Eight months, later following the treatment, the patient did not have Ab or Kp positive cultures. His wound had closed completely and did not have any secretions, and his pain had also disappeared.
• An examination of the patient's "blood, stool, urine, and saliva samples" revealed the absence of active phage viruses in the patient's bacterial isolates.

Research Methodology

Bacteriophage Therapy Media Analysis

• In the past two years, there has been more positive media attention towards bacteriophage therapy. For example, there are many announcements regarding partnerships and mergers in this space. Recently, C3J Therapeutics and AmpliPhi Biosciences merged to bolster the development of bacteriophage therapeutics.
• Breakthroughs are being announced regarding successful therapies. Recently, Armata Pharmaceuticals confirmed to have successfully created a bacteriophage therapy for "multidrug-resistant Pseudomonas aeruginosa infection."
• Another report by PR Newswire indicates that BimX Limited, an Israeli-based company, licensed a new line of bacterial targets from JSR Corporation to combat primary Sclerosing Cholangitis (PSC), a liver disease.
• A team of Israeli scientists won a Nobel Prize in 2018 for their phenomenal work in developing an anti-cancer drug based on bacteriophage therapy and other technologies. However, there is more proof needed to ascertain the accuracy of the drug as an effective treatment for patients with cancer.
• A two-day conference involving departments from the U.S. Food and Drug Administration (FDA) and the National Institutes of Health (NIH) was held in July 2017 to share information with the medical and scientific sectors regarding regulatory and scientific issues around bacteriophage therapy.

Public Perception Around Bacteriophage Therapy

• While the general sentiment shows some belief in this kind of therapy treatment, still people are not convinced fully. In this regard, there are still concerns that bacteriophage therapy has to evolve further from individual cases and clinical trials to evidence-based studies that show the therapy is safe, effective, and can be adopted as a routine medical practice.
• Expert opinions show that while this type of therapy promises to solve various drug-resistant illnesses, it is still far from replacing relatively cheaper antibiotics. Moreover, they are useful for certain applications like ear infections and diabetic foot ulcers, but not all.
• The public is willing to try bacteriophage therapy. Peter Knox has been battling an antibiotic-resistant infection for over 16 years and has had double lung transplants, but his condition keeps on reoccurring. He is now willing and ready to have the therapy; however, it is unavailable in his country.
• Another example involves the University of California-San Diego (UCSD) infectious disease epidemiologist, Steffanie Strathdee, who looked for bacteriophage therapy to treat her husband, who was suffering from a multi-drug resistant superbug.
• The public feels that humans need to evolve faster and be smarter than these antibiotic-resistant bacteria, which evolve naturally to develop a cure. In the meantime, there is no imminent cure, according to Dr. Peter Beyer, a senior advisor at the World Health Organization.
• The public still fears whether bacteriophage therapies can harm their bodies in ways that are not directly related to toxicity due to their unpopularity. Moreover, it is not approved for use in the U.S. and Europe; therefore, the public is not ready to try these therapies until they are approved as effective treatment options.

Research Methodology