Unprecedented case series advance the promise of phage therapy

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Newswise – An international team of researchers, led by scientists from the University of California San Diego School of Medicine and the University of Pittsburgh, reports promising results from the largest case series of patients to date treated with bacteriophage for antibiotic-resistant infections.

Findings published in the June 9, 2022 online issue of Clinical infectious diseases.

Nontuberculous mycobacterial (NTM) infections are increasingly common in patients with cystic fibrosis or other chronic diseases that damage or destroy the bronchi of the lungs – the network of tubes that carry oxygen and other gas in the organs.

Treatment of NTM infections, especially those caused by Mycobacterium abscessus, are challenging due to the growing resistance of bacteria to antibiotics, long the standard of care. The Centers for Disease Control estimates that nearly 3 million antibiotic-resistant infections of all kinds occur in the United States each year, resulting in 35,000 deaths.

Bacteriophages are viruses that have evolved to target and destroy specific bacterial species or strains. Phages are more abundant than all other life forms on Earth combined and are found wherever bacteria exist. Discovered at the beginning of the 20th century, they have long been studied for their therapeutic potential, but more and more with the rise and spread of bacteria resistant to antibiotics.

In 2016, scientists and physicians at UC San Diego School of Medicine and UC San Diego Health used experimental intravenous phage therapy to successfully treat and cure their colleague Tom Patterson, PhD, who was about to die from a multidrug-resistant bacterial infection. Patterson was the first documented case in the United States to use intravenous phage to eradicate a systemic bacterial infection. Subsequent success stories helped establish the Center for Innovative Phage Applications and Therapeutics (IPATH) at UC San Diego, the first such center in North America.

“We believe this is a groundbreaking subject and study that evolved from our original case report on Tom Patterson,” said co-corresponding author Constance Benson, MD, professor of Medicine and Global Public Health at UC San Diego School of Medicine. “It promises to be highly cited as we at IPATH and others work to expand the uses of phage therapy.”

Currently, these uses are limited, in part because each phage species seeks out and destroys a single bacterial species and the current arsenal of known therapeutically useful phages is relatively small. As a result, phage therapy testing is currently limited to experimental treatments where all other viable alternatives fail or have failed.

The new study involved a cohort of 20 patients with complex, antibiotic-refractory mycobacterial infections. All patients had varying underlying conditions; most had cystic fibrosis (CF), a progressive inherited disease that causes severe damage to the lungs and other organs. Currently, there is no cure for cystic fibrosis. The average life expectancy for people with cystic fibrosis who live to adulthood is about 44 years.

Patients participating in the study qualify under the U.S. Food and Drug Administration’s “compassionate use” provision, which allows investigational drugs or products to be tested for life-threatening conditions when no therapy comparable or satisfactory alternative is available.

Benson, corresponding co-author Graham F. Hatfull, PhD, Eberly Family Professor of Biotechnology at the University of Pittsburgh, and colleagues screened 200 patients with symptomatic lung disease to identify bacterial strains that may be sensitive to phages, and identified 55 strains.

Phages were administered to the 20 study participants intravenously, by aerosolization via a nebulizer, or using both methods twice daily for an average of six months, although some patients received shorter or longer depending on the clinical or microbiological response.

Patients were monitored for adverse effects, signs of symptomatic improvement or reduced bacterial presence, emergence of phage resistance, and/or phage neutralization by the patients’ immune system.

Results

The authors reported no adverse reactions to phage therapy in any of the patients, regardless of the type of bacterial infection, the types of phages used, or the method of treatment. Eleven of the 20 patients showed some improvement in symptoms or reduced bacterial presence. Five patients had inconclusive results and four showed no response to treatment.

In eight patients there was a noted increase in neutralizing antibodies, which may have contributed to the lack of response to treatment in four cases. Eleven patients were treated with a single phage, without any indication of phage resistance being observed.

“Given the complexity and wide variation of these patients and their individual conditions, it is not possible to draw general conclusions except that phage treatment of mycobacterial infections is promising and should be explored further. “, Benson said, “particularly for treating patients with few or no other good options.

Hatfull said the study provided several insights into how therapeutic phages could be used effectively.

First, he said, it underscored the need to greatly expand the repertoire of useful phages, whether growing them from isolated strains or creating synthetic versions, a company emerging.

Second, the lack of phage resistance was encouraging, supporting the use of a single phage treatment, although when more than one suitable phage is available the authors suggested cycling their administration to circumvent neutralization. by the patient’s immune system.

Third, the optimal delivery of phages, whether intravenously or by aerosolization, may depend on the nature of the infection and whether the patient’s immune system is compromised.

Fourth, because phages appear to be well tolerated with no adverse effects, higher doses and longer treatment periods might be possible and advisable.

“All of the limitations that we have observed and documented are not insurmountable,” Hatfull said. “These case studies suggest that phage treatments may be valuable tools for the clinical control of NTM infections.”

Co-author Robert Schooley, MD, professor of medicine and infectious disease expert at UC San Diego School of Medicine, who serves as co-director of IPATH and helped lead the clinical team that treated and cured Patterson in 2016, took a longer view:

“In phages, evolution has produced an effective bacteria killer, which holds enormous potential in the global fight against antibiotic resistance. This article is a preview of what could and can be. It starts with NTM infections, but the number of antibiotic-resistant bacterial species is large and growing. It’s another important step in a fight that will probably never end.

Co-authors include: Rebekah M. Dedrick, Bailey E. Smith, Madison Cristinziano, Krista G. Freeman, Deborah Jacobs-Sera, and Ghady Haidar, University of Pittsburgh; Yvonne Belessis, University of New South Wales, Australia; A. Whitney Brown, Inova Fairfax Hospital, Virginia; Keira A. Cohen, Johns Hopkins University School of Medicine; Rebecca M. Davidson and Jerry A. Nick, National Jewish Health, Denver; David van Duin, University of North Carolina; Andrew Gainey, Prisma Health Children’s Hospital-Midlands, SC; Cristina Berastegui Garcia, Hospital Universitari Vall d’Hebron, Spain; CR Robert George, John Hunter Hospital, Australia; Winnie Ip, Austen Worth, Kirsi Malmivaara, James Soothill, Mikael Skurnik and Hellen Spencer, Great Ormond Street Hospital, London; Jonathan Iredell and Brendan J. McMullan, Sydney Children’s Hospital, Australia; Ameneh Khatami and Paul D. Robinson, Westmead Children’s Hospital, Australia and University of Sydney; Jessica S. Little and Daniel A. Solomon, Brigham and Women’s Hospital, Boston; David E. Michalik, Miller Hospital for Children and Women, Long Beach, Calif.; Andrea Moscatelli, Instituto Giannina Gaslini, Italy; Maria G. Tupayachi Ortiz, University of Miami; Hari M. Polenakovik, Wright State University, Ohio; and Peter Wark, University of Newcastle, Australia.

Funding and support for this research came, in part, from the National Institutes of Health (grants GM131729, HL146228, and AI154546), the Howard Hughes Medical Institute (GT12053), the Cystic Fibrosis Foundation (HATFUL19GO, NICK20Y2-SVC, and NICK20Y2- OUT), the Fowler Fund for Phage Research, the National Heart Lung and Brain Institute (HL139994), the Burroughs Wellcome Fund Career Award for Medical Scientists, the Jane and Aatos Erkko Foundation, the Mallory Smith Legacy Fund, and the UC San Diego Chancellor’s Fund .

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Disclosures: Hatfull is a consultant for Janssen Pharmaceuticals and receives a grant for work not directly related to it. Dedrick and Hatfull are co-inventors of the patent applications related to the use of phages for the treatment of NTM infections filed by the University of Pittsburgh of the Commonwealth System of Higher Education. Van Duin is a consultant for Actavis, Tetraphase, Sanofi-Pasteur, MedImmune, Astellas, Merck, Allergan, T2Biosystems, Roche, Achaogen, Neumedicine, Shionogi, Pfizer, Entasis, QPex, Wellspring, Karius and Utility; receives an editor’s allowance from BSAC; and funding of unrelated projects by the NIH, Merck, and Shionogi. Cohen has received consulting fees from Insmed, Hillrom, Paratek, Microbion and AN2. Haidar receives a grant unrelated to this study from Karius and Allovir. Schooley is a paid consultant for VIR Biotechnology and LysNtech and holds stock options in Antiva Biosciences and CytoDyn; he previously served as an unpaid member of AmpliPhi’s Scientific Advisory Board.

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