Isabelle Carnell-Holdaway was only 15 when, in 2017, the cystic fibrosis she had endured all her life forced her to have a double lung transplant.
CF patients depend on antibiotics every day to keep at bay infections that scar their lung tissue. After her transplant, with her immune system suppressed to prevent rejection of the new organs, Isabelle was even more reliant on the drugs.
But infection did take hold. A strain of the bacteria mycobacterium abscessus, resistant to antibiotics, swept through her body. Her operation wound became livid and red. Her skin erupted in weeping sores.
As the drugs failed, consultants at London's Great Ormond Street Hospital prepared for the worst. Then her mother, Jo, after carrying out her own research, asked about using bacteria-killing viruses, known as phage, to do what the antibiotics could not.
The doctors worked with scientists in the US to pair the bacteria ravaging Isabelle's body against a library of such phage and, like a deadly dating game, a single killer match was found. From that, two others with potential were manufactured and genetically tweaked to help ensure that they too did not become a victim of bacterial resistance.
The three-phage cocktail proved a spectacular success. In weeks, Isabelle's wounds closed and healed and she was up and about. And though it is hard to deliver widely, today phage therapy is one of several strategies being deployed to fight the medical calamity of antibiotic resistance or AMR.
Last week, world leaders called for a new international treaty to improve pandemic preparedness – but for all Covid's impact, many consider AMR to be the true crisis facing humanity.
Antibiotics – which kill harmful bacteria, not viruses – have underpinned medicine since the accidental discovery of penicillin in 1928, treating potentially fatal infections stemming from minor scratches to major surgery.
Almost as soon as he made his miraculous breakthrough, however, Alexander Fleming realised the clock was ticking. As he put it in a Nobel lecture in December 1945, "it is not difficult to make microbes resistant to penicillin".
As soon as they were exposed to antibiotics, bacteria began to prioritise genetic mutations that conferred resistance; with more time and ever more exposure, the problem of resistance grew and grew.
A pharmaceutical vicious circle then emerged: it became increasingly hard to develop new drugs to outrun AMR, so existing antibiotics were used less, making them less profitable and encouraging drug developers to ditch research. Eventually, patients like Isabelle started to be consumed by bacteria for which there was no antibiotic answer.
Worldwide, low estimates put AMR deaths at 700,000 each year. In Asia, neonatal sepsis now accounts for almost a quarter of a million baby deaths annually.
"Antimicrobial resistance has worsened in the last decade, rendering most antibiotics obsolete," notes Jeeva Sankar from the department of paediatrics at the All India Institute of Medical Sciences.
International travel and the way different bacteria easily transfer resistance between one another mean that, as with Covid, AMR is not a problem that can easily be confined to one corner of the globe. Keeping tabs on the resistant bacteria we may be carrying inside us is, as microbiologist Jordi Vila once told me, impossible: "Are you going to give everyone who arrives [at Heathrow] a rectal swab?"
No wonder AMR, which Health Secretary Matt Hancock calls the "silent pandemic", is on the agenda for the G7 summit in Cornwall in June. A report by Lord O'Neill predicts that if nothing is done, the cost by 2050 will be 10 million deaths per year and a cumulative US$100 trillion ($141.6t). That's four times worse than Covid, the toll of which so far stands at 2.6 million deaths and US$24t. But all is not lost.
No new class of antibiotics has been brought to market for decades, but that may be changing.
"We're getting some new antibiotics, it's proving possible to develop them," says Laura Piddock, professor of microbiology at Birmingham University and scientific director at the Global Antibiotic Research and Development Partnership (GARDP).
Some 43 new antibiotics are in the drug "pipeline" – with 13 at the final phase 3 trial hurdle (which about 60 per cent typically cross). The good news is that many of these new drugs target bacteria that are deemed critical threats; the bad news is that they do so in the same old way, meaning resistance is likely to recur sooner.
Alternative treatments for bacterial infection, such as phage therapy, offer another route.
Researchers are looking at ways of protecting us by reducing the virulence of bacteria, priming our immune system or tweaking the beneficial microbes we all host in our bodies. But timelines are long, and while results may eventually prove spectacular, nothing can match the simplicity and effectiveness of antibiotics today. Apart, perhaps, from vaccines.
Covid has showcased the power of vaccines to the world. If vaccines could prevent infections in the first place, we wouldn't need antibiotics to treat them.
"E. coli is a major problem," says David Livermore, Professor of Medical Microbiology at UEA. "It accounts for 75-80 per cent of urinary tract infections. About a third of all blood poisoning. Johnson and Johnson are looking at vaccines targeting it. That would be a big gain."
GSK has confirmed that it, too, has "several vaccine projects targeting priority AMR pathogens", notably staphylococcus aureus (known as the "superbug" MRSA when resistant), clostridium difficile and gonorrhoea. As things stand, says Livermore, "we really are running desperately low on treatment options" for the last of these.
The possibilities are significant. Vaccines could be extended to treat "anything that causes an infection in humans that does not normally live in or on the human body", says Piddock, from food poisoning to typhoid, leaving the world far less dependent on antibiotics.
Antibiotics in farming
Everyone working on AMR agrees that the use of antibiotics in farming also requires urgent attention.
Across the globe animals reared intensively are routinely given antibiotics to check infections and promote growth.
"It's a huge issue … an international disgrace," says Tim Walsh, director of biology at a new £100 million ($197m) research institute at Oxford University that is targeting AMR.
"We currently use thousands of tonnes of ampicillin around the world as a growth promoter. This is the same antibiotic that the WHO advocates as the primary treatment for neonatal sepsis."
Some 94 per cent of sepsis-causing bacteria are now resistant to ampicillin.
Walsh thinks we have been looking at AMR the wrong way round. Instead of developing new antibiotics for people, he says, the Oxford Institute's "frontline programme is to design novel drugs that we can use in global farming". That will then remove human-use drugs from farming.
Covid 'a massive shake-up'
Increasingly, such conversations are not falling on deaf ears. What was niche interest a decade ago has become mainstream politics today, notably in the UK.
"We have a new Government and they're taking it seriously," says Walsh.
"Covid has been a massive shake-up," says Piddock. "Politicians have realised that global public health underpins the economy, not the other way around. AMR is back on the table this year."
Money is beginning to return to antibiotic research, often thanks to big government – notably America's Biomedical Advanced Research and Development Authority, or Barda.
At the other extreme, a host of small pharma companies, often backed by venture capitalists, are stepping in. According to the Pew Trust, of the 38 companies with antibiotics currently in clinical development, only two rank among the top 50 pharmaceutical companies by sales. Where the giants have stepped back, minnows have emerged.
When I first wrote about AMR almost a decade ago, it was impossible to avoid martial language. It was "a war" between bacteria and mankind, one we were losing. Eight years on, it remains a critical issue, but in the grinding way of human affairs, it has slowly scaled the ladder of issues that matter.
While much remains to be done there are, as above, some reasons to be positive. In particular, Covid has provided a previously unthinkable wake-up call, warning what can go wrong if nothing is done, and right when we put our minds to it.
"Covid showed we are unprepared for a pandemic emergency," says Walsh. "But it has also shown that we are better working together across the planet. One of the reasons why AMR is on the G7 [agenda], is because people now realise that, if it's not checked, it will make Covid look like a Sunday school picnic, both in terms of human life and in economic impact as well."