Recent News 67 : In Lyon, phage therapy against antibiotic resistance

In Lyon,phage therapy against antibiotic resistance

At the Croix-Rousse Hospital in Lyon, the Reference Center for Complex Osteoarticular Infections (CrioaC) treats patients at a therapeutic impasse using viruses found in the environment.

Professor Tristan Ferry examines the scar of Alexandre Vuitton, a patient he is treating for a osteoarticular infection following a knee prosthesis. © Bastien Doudaine.

"You're experienced, would you like more explanations?" asks nurse Koudedia Fall to Alexandre Vuitton. This is the third consecutive week that this 51-year-old patient has traveled from the Jura region, where he lives. He waits with a smile on his face to be picked up for the procedure he is scheduled to undergo. Like every Thursday, it's a frenzy in this day hospital perched on the heights of Lyon. "Working here is generally much quieter than in the inpatient unit: but Thursdays are crazy!" laughs Irmine Achikpa, a nurse here for ten years. Since the Croix-Rousse hospital is a reference center for bone and joint infections, the facility sees an influx of the most complex infections, many of which involve bacteria that are multi-resistant to antibiotics. But Thursday is reserved for them: Professor Ferry's team, the infectious disease specialist who coordinates the center, meets with a multidisciplinary team to devise the most appropriate therapeutic strategy. The various doctors then visit each patient. Among the options being considered to overcome these stubborn infections is a still-infant treatment pioneered by the department in France: phage therapy, based on bacteriophages, natural viruses that only attack bacteria.

This is the protocol that Alexandre Vuitton has been using for several weeks: today, he will receive his final injection, hoping that the phages will eradicate or at least permanently contain the golden staphylococcus that has colonized his knee. As is often the case in these situations, the bacteria developed around a prosthesis, fitted in 1996: then aged 24, he narrowly escaped amputation following an osteosarcoma. His life continued as usual, until the end of 2022: while going to the bathroom from his bed, a violent pain in his knee seized him. Having lived in Vietnam for twelve years, he was urgently repatriated after having nearly died, in his words. "All my organs were failing one after the other." Surgical enemas and antibiotic treatments then followed: the infection receded before recurring on December 20, 2023, “one year to the day after the first attack” .

Therapeutic impasse

Estelle Lépine, a pharmacy technician, notes the batch numbers of the phage therapy bottles and ensures their traceability. ¢ Bastien Doudaine.

At the Hospices Civils de Lyon, Tristan Ferry then suggested that she try phage therapy, which the hospital has been practicing sparingly for almost ten years: since the treatment is not yet authorized in France, it is only provided in cases of therapeutic impasse and in a very controlled manner. "These are patients who are sometimes in the doldrums, having been on antibiotics for years, so they naturally have a lot of hope in the treatment ," notes Irmine Achikpa. "We

 sometimes have to re-explain to them how the treatment works. Even if Professor Ferry takes a lot of time to do it, it's a lot of information and I often advise them to bring a relative who can witness the exchanges!" For the infectious disease specialist, this interface role played by nurses "is essential to raise questions and concerns" surrounding this little-known type of treatment.

Yet, phage therapy is not new: it has been discovered for over a century! To understand this, we have to go back to 1917: antibiotics did not yet exist and the Frenchman Félix d'Hérelle, a biologist at the Pasteur Institute, realized that certain viruses present in the environment – ​​lakes, sewers, etc. – had the ability to kill bacteria.

"These phages, called lytic, recognize certain bacteria, introduce their genetic heritage, multiply and produce an enzyme, lysine, which makes the bacteria explode," explains Professor Ferry, who is passionate about the subject. The hundreds of new phages released will infect neighboring bacteria." A few years later, in 1928, penicillin was discovered: it was the rush towards antibiotics and their production, in which Western Europe invested massively as part of the war effort. Phage therapy, which took longer to develop, was left aside. Only Eastern Europe continues to use it: in Georgia, the Eliava Institute, dedicated to phage therapy, still exists to this day and phages are sold in all the country's pharmacies. History even tells that these viruses gave the Russians an advantage in the Battle of Stalingrad, who were able to fight the cholera epidemic thanks to the phages, unlike the Germans.

The injectable phage solution is reconstituted in a clean environment, under a fume hood, by Dr. Thomas Briot, pharmacist responsible for preparing these products, and Estelle Lépine, pharmacy technician. ¢ Bastien Doudaine.

Today, the renewed interest is explained by the urgency of finding solutions to the wave of antibiotic resistance that is gradually sweeping across Europe and will, according to WHO forecasts, cause "more deaths than cancer in 2050." A "slow-moving tsunami ," according to Professor Ferry, which he has seen progressing since he took over as head of CrioaC ten years ago. "In our hospitalization unit, half of the patients suffer from infections due to multi-resistant bacteria," he notes. The causes are "the globalization of trade, travel, industry ," which facilitate the migration of these bacteria, whose genetic makeup has adapted. In an aging Europe, they find hosts within our populations favorable to their development: the installation of implants and prostheses to accompany the extension of life expectancy facilitates the introduction of bacteria.

Groping forward

Marlène Mazuit, a radiographer, helps Alexandre Vuitton breathe into the mask containing Méopa, a gas mixture that will help him relax and be less painful. ¢ Bastien Doudaine.

Seeing his helplessness in the face of these delicate cases and knowing the principle of phage therapy, Tristan Ferry turned in 2014 to Phaxiam , then Pherecydes Pharma, the only start-up in France and one of the only ones in the world to develop phages. "Few launch on the market, because phages are collected from living organisms, they cannot be patented like any other drug: only the purification method can be ." A partnership is formed and the manufacturer begins to supply phages to the hospital - depending on the phages and the cases, the procedure differs: it is either part of a compassionate access authorization (AAC), validated by the ANSM and reimbursed, or outside of AAC where the treatment is provided free of charge, or as part of a clinical trial conducted with Phaxiam (in phase II). When none of their phages are suitable, Professor Ferry looks elsewhere – in Belgium or the United States, for example.

Viruses must sometimes, depending on their origin, be checked upstream "to check for endotoxins that could give the patient a fever if they are not purified enough ," explains Dr. Briot, a hospital pharmacist. The morning they are administered, they are prepared at the pharmacy: generally injected as a cocktail of two or three phages, they are mixed and diluted in sodium chloride, "then brought and injected directly," explains Sylvie Perret, a nurse, " except on weekends when they are kept in the refrigerator for a maximum of three days ," at 4°C. In this day hospital, injections are often performed under ultrasound, in the radiology room: this morning, Dr. Jade Miailhes is in charge of Mr. Vuitton's procedure. "We see with the patient upon arrival whether they would like the doctor to offer them premedication, such as painkillers, because it can be very painful . " This is what the 51-year-old gentleman asked after suffering a lot during his first treatment.

Concentrated, Dr. Jade Miailhes, radiologist, injects the phages under ultrasound, into Mr. Vuitton's knee joint. ¢ Bastien Doudaine.

In about ten minutes, the radiologist performs a puncture to analyze the fluid present in the effusion, and injects the precious mixture. Depending on the method of administration, the procedure can be performed by nurses. "This happens in conventional medicine ," explains Sylvie Perret. When I worked in hospital, I sometimes performed phage aerosols for a person suffering from a serious lung infection. We also take care of intravenous injections, which are given over several consecutive days ." This is what Mr. B, who suffers from a recalcitrant pseudomonas infection, underwent today for a check-up. "The scar is beautiful, but it is still a little early to know if the little creatures have had an effect ," says Professor Ferry to this 76-year-old former farmer.

Following treatment, patients return regularly for check-ups and to assess the progress of the infection: "they are often included in research protocols, so doctors need other information; we sometimes have to fill up to ten additional tubes for blood tests !" continues Sylvie Perret. "And we also monitor the dressing and its coloring." Because many unknowns remain surrounding phage therapy: dosage, method of administration, associated antibiotics, etc. "It's still empirical," explains Professor Ferry. Especially since "the future of the phage in the body remains a mystery ," adds Dr. Briot. "Unlike other drugs whose presence in the body diminishes over time, phage therapy works thanks to the self-replication of the virus ." In 2022, 70% of patients treated with phage therapy in the department experienced an improvement in their condition. "We are hopeful that these promises will be confirmed ," concludes Sylvie Perret.

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