French Hospital Starts Program to Fight Antibiotic Resistance

Anne-Gaëlle Moulun

April 14, 2022

LYON, France — At the end of last year, the Lyon Civilian Hospitals (HCL) in France obtained €2.85 million in funding for the PHAG-ONE phagotherapy project. HCL developed the project in response to the call for research proposals, titled "Antibiotic Resistance: Understand, Innovate, Act," by the French National Research Agency. Frédéric Laurent, PhD, microbiologist and head of the Bacteriology Department at the Institute of Infectious Agents in Lyon, explained the project to Medscape Medical News. He also spoke about the PHAGEinLYON program, which is supported by the HCL, the International Center for Infectious Diseases Research, and Claude Bernard Lyon 1 University.

The Machinery of Bacteria

Antibiotic resistance is on the rise, causing therapeutic impasses with increasing regularity. Phagotherapy offers a promising therapeutic alternative. "Phagotherapy is a treatment that uses phages, ie, viruses that are active only against bacteria and have no effect on human cells. They bind to bacteria, injecting their DNA into them, and then use the machinery of the bacterium to produce bacteriophages, which make enzymes that explode the bacterium to escape. This cycle takes place within half an hour. A single phage has the distinctive ability to release 1000 phages, which will in turn attack 1000 bacteria, so the system is self-sustaining until the bacteria are completely gone," explained Laurent.

Easy to Harvest

Each phage is typically active against one specific species or strain of bacteria. They are easy to harvest. They abound where bacteria proliferate, especially in wastewater. "We isolated the first phages we worked on from the lake at the Tête d'Or Zoo in Lyon," said Laurent. The phages are harvested, isolated, and then characterized genetically to determine which bacterial strains they are active against. They must then multiply and be purified before they are administered to a patient in the form of multiphage cocktails. "To multiply the phages, they must be placed in contact with bacteria. In the end, we obtain a large number of phages, but also a lot of bacterial debris and products secreted by the bacteria. The challenge," said Laurent, "is to purify the phages without this debris and these metabolites."

French Discovery

Discovered in France in the 1920s by Félix d'Hérelle, bacteriophages, or phages, were used from 1920 to 1940 before being replaced by antibiotics. Although phages were abandoned in France and Western Europe, they continued to be used in the Eastern countries of Georgia, Russia, and Poland, but the pharmaceutical production conditions that are used did not meet the strict standards required by the French and European health authorities, which prevented them from being used as injections. Thus, the phages produced in those countries are not approved in France or other Western European countries.

Therapeutic Impasses

Antibiotics, while still valued, have begun to show their limitations. More and more patients are developing infections associated with multiresistant bacteria. At HCL, the Reference Center for Complex Osteoarticular Infections in Lyon, resistance has been encountered in knee and hip prosthesis infections. "In an increasing number of patients, none of the antibiotics are active," said Laurent. "We now find ourselves at therapeutic impasses for some patients." He considers phages to be a promising therapeutic alternative, although their use remains limited.

Compassionate Use Only

"Currently, phages are not listed in the French Pharmacopoeia or European Pharmacopoeia and are not approved in France by the National Agency for Medicines and Health Products Safety (ANSM). The only possible use of these treatments is in a compassionate use context, strictly limited and overseen by the ANSM," said Laurent. To date, only 36 patients have received phagotherapy for osteoarticular infections or endocarditis in Lyon. "These are patients at the end of the line for treatment; the standard treatments resulted in therapeutic failure for them. Some of them have been able to return home following phagotherapy, even though [previously] they were no longer able to walk and were experiencing chronic pain, and some were on morphine."

The PHAG-ONE project is aimed at the isolation, production, purification, packaging, and quality control of therapeutic phages active against three species, Staphylococcus aureus, Staphylococcus epidermidis, and Escherichia coli, to meet all the regulatory requirements for human use. The resulting therapeutic phages will be used to treat infections caused by multiantibiotic-resistant bacteria in a compassionate use context and in clinical trials.

Training Phages

"For S aureus, we have already selected the three most promising phages, and we are working on validating the production and purification processes. For E coli, we have isolated the first twenty or so phages. Now we will have to select the ones that have the most relevant activity, in conjunction with the French National Reference Center for Antibiotic Resistance, which is providing us with the resistant strains circulating in France. We already know we have candidate phages that target the most resistant and most epidemic clones in Europe, which is good news," said Laurent.

"We are also doing 'phage training,' " he added. "By subculturing several phages together many times in the presence of certain bacterial strains, we force the phages to exchange their genetic material to produce even more active 'superphages.' The idea is to obtain phages that hit harder and hit more strains of the same species," he said. Laurent's team is also working on phagograms (that is, techniques that a laboratory can implement easily to determine which phage to use against which bacterium).

Multidisciplinary Meeting

Concurrently, the team, headed by Tristan Ferry, MD, PhD, an infectious disease specialist at the HCL and copilot of the PHAGEinLYON program with Laurent, has set up a multidisciplinary consultation meeting for phagotherapy. "We infectious disease specialists, microbiologists, and pharmacists talk among ourselves to determine whether patients are candidates for phagotherapy," said Ferry. "We take stock of the phages we have or don't have available and review how to treat the patient, the administration rate, etc. After that, we perform repeated injections, which means additional work for us and for the pharmacy that prepares the phages."

In addition to treating patients in Lyon, the HCL team also acts in a support capacity to set up treatments for patients outside the university hospital. "Colleagues from other hospitals in France have asked us for our opinion, our advice, and to provide procedures. Our idea is to position ourselves as a reference center for phagotherapy in France," said Ferry.

Other work has been initiated within the PHAG-ONE consortium in collaboration with the French National Center for Scientific Research team headed by Rémy Froissart, PhD, in Montpellier or that led by Charlotte Brives, PhD, in Bordeaux (Émile Durkheim Center), which is focused on epistemologic frameworks and methods and techniques regarding the acquisition of knowledge related to the development of this biomedical innovation in France.

"Currently, there are no other hospitals in France developing a public and academic production of phages like we are doing," said Laurent. "Only one private pharmaceutical company is producing therapeutic phages in France — Pherecydes Pharma. My colleague Tristan Ferry is going to launch a clinical trial in collaboration with them called PhagoDAIR." This phase 1/2 clinical trial will examine the treatment of osteoarticular infections of prostheses caused by S aureus. The protocol was approved by ANSM in December 2021.

"We are in contact with other foreign producers that want to set up this same type of trial in France," Laurent concluded.

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