The first antibiotic was discovered by Paul Ehrlich in 1909 and cured syphilis-infected rabbits. At that time about 10% of the population of London were infected with syphilis and there were no effective treatments. Despite the tedious injection procedure and side effects, Salvarsan, together with the less toxic derivative Neosalvarsan, enjoyed the status of the most frequently prescribed drug until its replacement by penicillin in the 1940s. The postwar period was the beginning of a 20-year golden age of antibiotic discovery, with a large number of effective new antibiotics entering into clinical use.
But the problem of antibiotic resistance has been increasingly recognised over the past 30 years, with the chief medical officer of England, Dame Sally Davies, in 2018 repeating her warning of the post-antibiotic apocalypse facing modern medicine as we run out of effective antibiotics to treat life-threatening infections. The recent success in treating 17-year-old Isabelle Holdaway – who was left with an infection that could not be cleared by antibiotics after a lung transplant – with bacteria-killing viruses offers some hope. But it also raises the question as to how this therapy works and whether it can help to overcome the problem of antibiotic resistance.
The discovery of bacteria-killing viruses is attributed to both Frederick Twort in London in 1915 and Félix d’Hérelle in Paris in 1917; the latter gave them the name bacteriophage, literally “bacteria eaters”. It was d’Hérelle who made the important observation that he could isolate the invisible bacteriophage in the faeces or urine of patients recovering from dysentery or typhoid. He soon became determined to develop therapies against bacterial infections and was soon taking his wife and young children on hazardous journeys chasing epidemics around Europe so that he could recover more bacteriophage.
He achieved his first success in 1919 with the successful treatment of a 12-year-old boy suffering from dysentery at the Hôpital des Enfants-Malades in Paris, using a bacteriophage isolated from a faecal sample of another dysentery patient. He ingested the phage preparation himself, to test its safety, before administering it to the boy, and soon afterwards cured three additional dysentery patients, using the same phage preparation. Despite this success, bacteriophage therapy was largely abandoned in western countries due to the ready availability of cheap and effective antibiotics, but it continued to be developed in eastern Europe during the cold war years, as they had little access to these antibiotics. Yet the effectiveness of bacteriophage therapy has only recently started to be tested in rigorous clinical trials.
In addressing the question of its future prospects, we have to consider how bacteriophage therapy is used in practice. In Isabelle’s case, the bacteria causing her infection, Mycobacteria abscessus, was sent to the US to be tested for its sensitivity to killing against a collection of more than 10,000 bacteriophage. Because bacteria can easily become resistant to a single bacteriophage, a cocktail of several bacteriophages has to be used. Even then, of the three bacteriophages used, testing showed that the bacteria culture was resistant to two of the three bacteriophages and only partially sensitive to the third. Isabelle was treated with the bacteriophage cocktail sent from the US and fortunately continues to improve clinically.
In order to use bacteriophage therapy as an alternative to antibiotics there are several obvious problems. Companies may not invest in the cost of bringing this technology to market as there are difficulties in patenting natural products such as bacteriophage; there are regulatory challenges to overcome; having to change the composition of the bacteriophage cocktail to overcome resistance may impose additional costs; and the number of patients using any one bacteriophage cocktail may be very small.
Public bodies could take over development in a non-profit environment, but would still face many of the same problems. Bacteriophage therapy is also unlikely to be feasible for patients with a life-threatening, acute bacterial infection such as sepsis, as there would simply not be time to test the isolate against a collection of bacteriophages (even if one exists anywhere in the world), formulate an effective cocktail, then ship it to the patient’s location.
Isabelle’s story is good news, and bacteriophage therapy will make a contribution to addressing the problem of antibiotic resistance in some bacteria-causing infections. However this will only be as part of a multifaceted approach. We will need to use newly discovered antibiotics, vaccines and natural protein antibiotics (called bacteriocins, which have been made by bacteria for thousands of years), if we are to face the challenges that resistance brings.
• Richard James is an emeritus professor at the University of Nottingham and the founder of the Developing Novel Antibiotics Consultancy
