Phages – the answer in the battle to beat superbugs?
Most mothers-to-be expect their lives to change for ever with the birth of their first child, but Catherine Farrer could not have prepared for the shock news delivered to her half-way through her first pregnancy.
It had been otherwise straightforward until a routine mid-pregnancy scan at 22 weeks.
‘I was told my daughter had an echogenic bowel, where the bowel looks brighter than normal on the ultrasound due to an abnormality,’ recalls Catherine, 35, who works part-time for a City financial services regulator and lives in East Dulwich, South London, with her husband Giles, 37, an oil and gas industry analyst.
An echogenic bowel is a marker for a number of conditions including cystic fibrosis, a genetic disorder that causes mucus to build up in the lungs and digestive system, affecting their function.
Although life expectancy has risen thanks to modern medicine, many patients do not live beyond their 40s.
The diagnosis of cystic fibrosis was confirmed after Kate was born nearly five years ago. Her arrival was the start of a roller coaster ride of health scares that has meant more than 50 courses of antibiotics already.
While healthy lungs are able to clear bacteria, in cystic fibrosis they can’t, which means bacteria are able to colonise the mucus. And some of these pathogens are very difficult to treat.
‘Kate recently suffered an infection that lasted for 18 months,’ says Catherine.
‘In that time she had 14 courses of oral antibiotics, two weeks of two different types of intravenous antibiotics and two months of antibiotic treatment with a nebuliser spray into her nose. In the long term, she is likely to become infected with bacteria that are multiple antibiotic resistant.’
Caring for Kate has exposed Catherine and Giles to the worrying realities of antibiotic resistance.
More than 70 years of blanket antibiotic use for human and animal diseases has given rise to generations of superbugs — resistant bacteria that have mutated into new lethally infectious organisms impervious to antibiotic attack.
The more antibiotics are used to kill the susceptible bacteria, the more living space has been left for resistant bugs to flourish, creating a growing risk that infections contracted from grazed knees, chest bugs or routine surgical operations could become deadly.
However, there is another potential treatment that could help where antibiotics fall short: phage therapy.
Phage is the name for a virus that attacks bacteria. These can be cultured in a laboratory and then used to selectively infect and destroy those that cause disease.
Britain’s chief medical officer, Dame Sally Davies, recently issued dire warnings that antibiotic resistance is as big a threat to the long-term future of the human race as climate change.
Already an estimated 50,000 people in the UK are dying each year from antibiotic-resistant infections, according to the charity Antibiotic Research UK.
The lung condition tuberculosis, which was previously treatable with antibiotics, is re-emerging as a leading cause of death.
Urgent need for new treatments
The pressing need for new ways to tackle infection has led researchers to the promise offered by phage therapy — which is generally made to order by identifying the bacterium responsible for an infection, then finding the virus known to attack that particular pathogen.
Phages can be applied to the skin, swallowed or given intravenously, depending on the site of the infection.
Though they have been used successfully since the 1930s in the former Soviet Union, where antibiotics were scarce, in the West they fell out of favour. Now, however, phages are emerging as a life-saver here, with a growing number of reports of extraordinary recoveries among people engulfed by apparently untreatable infection.
Last month, phage treatment was given the seal of approval by the influential scientific journal Nature Medicine, which reported how phage therapy had helped save Isabelle Carnell-Holdaway, a 15-year-old girl from Faversham, Kent, who was dying from a drug-resistant infection following a lung transplant for cystic fibrosis.
Her successful treatment — having been given less than 1 per cent chance of survival, Isabelle is now studying for her A-levels and learning to drive — was the first time that Mycobacterium abscessus, the bacterium killing her, had been controlled by a phage.
‘Isabelle’s recovery is incredible,’ her mother Joanne told Good Health. ‘This time last year, we had been told that she would die.’ Another remarkable example of phages’ life-saving effect is the story of Tom Patterson, a U.S. scientist whose case was reported in Good Health two years ago.
This week his wife, Steffanie Strathdee, who is also a scientist, has published a book, The Perfect Predator, in which she recounts his miraculous recovery from a killer bug, Acinetobacter baumannii, he contracted on holiday in Egypt.
The bacterium belongs to one of the top 12 families of dangerous superbugs, according to the World Health Organisation.
Tom Patterson’s extraordinary recovery has led to the establishment of a Center for Innovative Phage Applications at the University of California San Diego, and the U.S. Food & Drug Administration (FDA) is likely to license an increasing number of requests for phage therapies.
Meanwhile, his story prompted a flurry of other heroic efforts to use phages to treat rampant bacterial infection and up to 12 lives are now believed to have been saved.
There is also interest in using phages for everyday infections such as bacterial sore throats.
Breakthrough for British girl
In Britain, however, it is Isabelle’s story that has drawn the most excitement from doctors.
She had suffered repeated infections since cystic fibrosis was first diagnosed. In September 2017, she underwent a double lung transplant operation but then developed an infection caused by the Mycobacterium abscessus species.
After an eight-month fight to control it, specialist doctors at Great Ormond Street Hospital in London told her family in April last year that there was nothing more they could do.
The advice was to take Isabelle, who had a huge, unhealed wound from her double lung transplant and was covered in untreatable infected weeping sores, home and make her as comfortable as possible until she died.
‘She had complete liver failure and was a shadow of her former self,’ her mother Joanne, 51, a former bank official, told Good Health. ‘She wasn’t eating, drinking or talking. It was absolutely awful.
‘We had been given documents to pass on to the ambulance service saying not to try to resuscitate her but to let her die.’
There was just one glimmer of hope. Her doctors had discussed the possibility of using phage treatment after one of them met Graham Hatfull, a British-born professor of biotechnology at the University of Pittsburgh and a leading expert in phage therapy.
Isabelle’s doctor, Helen Spencer, a respiratory medicine consultant, contacted Professor Hatfull, who in November 2017 started working against the clock to find a phage that would kill the specific bacterium that was gradually killing Isabelle.
Treatment may lurk in the sewers
Phages can be found everywhere there are bacteria, including in the soil. Many live in sewage outlets.
The time-consuming element is to find the right phage for a particular bacterium.
To counteract this, Professor Hatfull has set up a programme in the U.S. to encourage school biology classes to become phage hunters for all sorts of bacteria.
Finally, in June last year, he contacted Dr Spencer to say he believed he had succeeded.
A supply of three phage solutions — one natural and two that had been genetically modified to improve their ability to attack Isabelle’s infection — was carefully placed in tiny bottles and flown to England.
With Isabelle readmitted to Great Ormond Street, the phage cocktail was first dabbed on the transplant wound to observe its effects. Within days, the cut began to show signs of a response. Inflammation reduced and there were early signs of it healing.
The next step was to risk dosing Isabelle with an intravenous phage infusion.
‘After ten days she was sent home from hospital and within three weeks there was a huge difference,’ says Joanne, who lives with her husband Paul, 53, a banker, and their younger daughter, who is eight.
Isabelle is now 17 and in the lower sixth. She managed to take maths and English GCSEs and has embarked on her A-levels.
‘For the first time, she’s doing the normal things for a girl of her age,’ says Joanne. ‘She’s got a Saturday job in a haberdashers and a lovely group of friends. It’s quite incredible considering what she was like last year when they had run out of options.’
It is not all plain sailing, though: Isabelle is still reliant on a complex cocktail of conventional antibiotics as well as the phages and one parent has to get up at 5am every day to begin the intravenous infusion.
Professor Hatfull is working on a fourth phage for her which may be decisive in finally destroying her infection.
‘I have been working in this field for 30 years and there have been cycles of interest in phages,’ he said.
‘I’m now quite optimistic that this enthusiasm will translate into what’s needed, which is good controlled trials which will tell us what diseases phages are going to be useful for.’
…And a boost for antibiotics
Professor Hatfull says treatment of some diseases may require cocktails of up to 20 phages, which would be prohibitively expensive.
But there is another potential benefit to using phages: they might make current antibiotics work better.
This appears to have been the case for Tom Patterson, according to his wife Steffanie, a U.S. scientist studying epidemics. As one of the doctors treating him explained: ‘Neither the antibiotic nor the phage were as effective on their own as they needed to be, but together — bingo.Stronger together.’
She adds: ‘Limited studies with animals had suggested that the benefits of using phages with antibiotics together was greater than either one by itself. Tom’s case provided human evidence that antibiotic-phage synergy was not only possible but extremely promising.’
Meanwhile, Catherine Farrer is determined to be prepared for the need for rapid action if a phage for Kate has to be identified.
‘We are thankfully still a long way from needing phage therapy, but it would be the next step,’ says Catherine.
Already, there are calls for more research funding here in Britain.
‘Phages could most definitely be used for common infections, but this means developing a pipeline from research to treatment, and that means funding,’ says Professor Martha Clokie, a microbiologist at the University of Leicester, who leads Britain’s phage research community.
‘What we need is a collaborative link between GPs and microbiologists to get things going.’
The Perfect Predator by Steffanie Strathdee, published by Hachette Books, £20.