Medications do not work: what happens after antibiotics? | Global

TThe first antibiotic that did not work for Debbi Forsyth was trimethoprim. In March 2016, Forsyth, a general care counselor in Morpeth, Northumberland, contracted a urinary tract infection. Urinary tract infections are commonplace, with more than 150 million people worldwide contracting one a year. So, when Forsyth saw his GP, they prescribed him the usual treatment: a three-day antibiotic cure. A few weeks later, when she fainted and started bleeding, she saw her GP, who again prescribed trimethoprim.

Three days later, Pete, Forsyth's husband, went home and found his wife lying on the couch, shaking, unable to call for help. He rushed her to A & E. She was put on a second antibiotic, gentamicin, and treated for sepsis, a complication of infection that can be fatal if she is not treated quickly. Gentamicin did not work either. Doctors have had Forsyth's blood tested, but such tests can take days: bacteria must be cultured and then several antibiotics tested for appropriate treatment. Five days after admission to the hospital, Forsyth was diagnosed with a multidrug-resistant infection. E. coliand given ertapenem, one of the so-called "last resort" antibiotics.

It worked. But the damage caused by the episode is persistent and she lives in constant fear of a recurrent infection. Six months after her collapse, she developed another urinary tract infection, again resulting from a stay in the hospital. "I had to accept that I would not go where I was," she says. "My daughter and my son said that they felt like they had lost their mother because I was not what I was." But Forsyth was lucky. Sepsis currently kills more people in the UK than lung cancer, and this number is increasing as we develop antibiotic-free infections.

Antimicrobial Resistance (AMR) – the process of evolution of the defense mechanisms of bacteria (and yeasts and viruses) against the drugs we use to treat them – is progressing so rapidly that the United have called it a "global health emergency". Every year, at least 2 million Americans contract drug-resistant infections. "Superbugs" spread rapidly, in part because some bacteria can borrow resistance genes from neighboring species through a process called horizontal gene transfer. In 2013, researchers in China discovered E coli containing mcr-1, a colistin-resistant gene, a last-line antibiotic that until recently was considered too toxic for use in humans. Colistin-resistant infections have now been detected in at least 30 countries.

"In India and Pakistan, Bangladesh, China, and South American countries, the problem of resistance is already endemic," said Colin Garner, CEO of Antibiotic Research UK. In May 2016, the British government Antimicrobial Resistance Review According to forecasts, 10 million people a year could be killed by antibiotic – resistant infections by 2050, more than all cancers combined.

"We have a good chance of reaching a point where, for many people, there is no [effective] antibiotics, "says Daniel Berman, head of Nesta's Global Health team. The threat is hard to imagine. A world without antibiotics means a return to an era without organ transplants, without hip replacement surgery, without much current surgery. This would mean that millions more women would die in childbirth; make many cancer treatments, including chemotherapy, impossible; and make even the smallest injury potentially lethal. As Berman told me, "Those of us who follow this closely are actually very scared."

Bacteria are everywhere: in our bodies, in the air, in the soil, covering every surface of their badtillions. Many bacteria produce antibiotic compounds – we do not know exactly the exact number of antibiotic compounds – probably as weapons in a microscopic battle to obtain resources between different strains of bacteria that has existed for billions of years. Because bacteria breed so quickly, they can evolve at an astonishing rate. Introduce the bacteria into a sufficiently low antibiotic concentration and resistance can appear in a few days. Penicillin resistance was first documented in 1940, a year before its first use in humans. (A common misconception is that people can become resistant to antibiotics – not bacteria, but bacteria.)

"Antibiotics have only been around for 70 or 80 years. Insects have been present on this planet for 3 billion years. And so, they have developed all kinds of survival mechanisms, "says Garner.

The problem is that today, antibiotics are everywhere. One in three antibiotics is prescribed every year to one in three patients – one fifth of these unnecessarily, according to Public Health England. For decades, many farmers have routinely injected livestock with antibiotics, both to help fatten them and to prevent infections (this practice is now banned in the EU, US, and the US). in Canada.) "Our generation is frightened by the power of antibiotics," says Jim O'Neill, the economist responsible for the government's review. "The problem is that we use them for things we should not need."

In the early decades of antibiotics, resistance was not a serious problem. We only found a new medicine. After penicillin revolutionized health care on the battlefields of the Second World War, the pharmaceutical industry entered a new era of antibiotic discovery. The companies have commissioned explorers, missionaries and travelers from around the world to bring back soil samples for new compounds. Streptomycin was found in a field in New Jersey; vancomycin, the jungles of Borneo; cephalosporins from a purification system in Sardinia.

But the golden age has been short-lived. New discoveries have slowed down. Antibiotic compounds are common in nature, but they can not kill bacteria without harming humans. Soon, major pharmaceutical companies began to cut funding for their antibiotic research services before stopping them altogether.

"In fact, the private sector is not investing enough to fund new research and development," says Tim Jinks, Wellcome Trust's Drug-Resistant Infectious Diseases Program Manager. The problem is simple: the ideal is that the antibiotics are inexpensive, but also used as little as possible. This is not an excellent commercial proposition. And given that antibiotic resistance may appear as early as the year after the introduction of a new clbad, a new antibiotic may only have an effective lifespan of 10 to 15 years – barely what to pay for years of development. "The numbers do not add up," he says.

There is always hope. In early 2015, researchers at Northeastern University, Mbadachusetts, announced the discovery of a new clbad of antibiotics in a Maine field. Called teixobactin, it is produced by a newly discovered bacterium, Eleftheria terraeand effective against a range of drug-resistant infections. Teixobactin was discovered by Slava Epstein and Kim Lewis with the help of an iChip, an ingenious device the size of a USB chip designed to solve a problem that biologists have been concerned with for decades: Of the billions of bacteria in the wild, only 1% of the species will grow in a petri dish. "We imagined a simple gadget," says Lewis. "You take bacteria in the soil, you sandwich them between two semi-permeable membranes and you essentially cheat them." Up to now, the couple has identified about 80,000 previously uncultivated strains with the help of device and isolated several new encouraging antibiotics.

Teixobactin is particularly promising for a simple reason: to date, no bacteria has been able to develop resistance to it. "When we released the document four years ago, several of my colleagues wrote me in e-mails:" Send me teixobactin, and I will send you resistant mutants, "says Lewis." J & # Wait again. "

Ishwar Singh remembers when he had heard about teixobactin: "It was January 7, 2015 on the BBC," he says. A reader at the University of Lincoln School of Pharmacy, Singh specializes in the development of new drugs. The news fascinated him. "Most antibiotics target proteins. Teixobactin acts on a lipid – the cornerstone of the cell wall, "he says. It attacks in several ways simultaneously, making resistance – at least until now – impossible. Singh shakes his head, marveling. "Nature has built such a beautiful molecule."

Today, Singh leads one of the many teams in the world developing teixobactin. I meet him on a wet January morning at his laboratory, where he wears rimless glbades and expresses sincere optimism. On a laboratory bench, Singh sketched the chemical structure of teixobactin in multicolored markers. Postdoctoral researchers walk around and test the purity of the samples. A doctoral student holds a small bottle containing a fine white powder and wide. "It's teixobactin," says Singh.

At first, producing such a small amount was difficult. Then, last March, the Singh team made a significant step forward: it replaced an amino acid difficult to produce by another alternative available at a lower cost. "There was not much to lose, because people were already saying it would not work," he says. But this is the case – tests have shown that it is effective against infections in mice. Singh estimates that the new structure has reduced production costs by 200,000 times.

Nevertheless, teixobactin has yet to be tested in humans in a few years. Putting on the market could take a decade or more, if it works. Zoliflodacin, for the treatment of multidrug-resistant drugs, is also advanced. Neisseria Gonorrhea, is currently in phase 3 testing on humans. In 2016, driven by the growing crisis, the United States, the United Kingdom and charitable organizations, including the Wellcome Trust, launched the CARB-X initiative, which provides $ 500 million in funding for promising new antibiotics. Through techniques such as rapid gene sequencing and metagenomics – which looks for a promising DNA in the environment and then clones it into a new bacterium – scientists have recently discovered a whole series of promising new compounds, including one found in the human nose. "Things are really happening, which is good," says Lewis. "But it's a little trickle."

Faced with the urgency of the problem, others are adopting more pragmatic approaches. One of the most promising is perhaps the simplest: give patients more than one drug at a time. "All we use for a common infection is monotherapy," says Anthony Coates, a professor of medical microbiology at St George's University Hospital in Tooting, London. On the other hand, polytherapy – which combines several complementary drugs – is the norm in many other fields. "AIDS is one, oncology is another," he says. "Why do not we do that with common bacteria?"

I meet him at his home in London. He has a calm and thoughtful attitude, which makes him all the more alarming. "The RAM is a disaster," he says. "We find that this deterioration is happening faster than I ever imagined."

Coates' specialty is so-called antibiotic resistance inhibitors – compounds that, when combined, can make bacteria resistant to antibiotic-sensitive drugs. In 2002, he launched a company, Helperby Therapeutics, to develop combination drugs; many are currently in clinical trials. "We are selecting thousands of combinations," he says. Until recently, the work was slow and laborious, done by hand, but advances in robotics and AI now allow the automation of much of it. which allowed for more complex combinations.

Why do therapeutic combinations not always work? "We understand some of the two solutions: you have a virus, you are drilling holes with an antibiotic, which allows the second antibiotic to enter," Coates says. "When three people act together, it's more complicated. Four and five: very complicated. But the operation of combinations is not as important as theirs.

One of the benefits of combination therapy is that many of the Helperby-screened drugs have already undergone the many required clinical trials before they can be administered to patients – "probably millions of people" – so that the risks of the drug are high. 39, lower medicine failure.

New drugs will not solve the problem of resistance alone. "Yes, it's important to get new drugs, but it's just managing the problem for another generation," O'Neill said. What managed to control the outbreak of MRSA is not a drug, but better hospital hygiene: wash your hands. O'Neill's greatest wish is not treatment at all. "If you said," You can only have one thing, "it's a state-of-the-art diagnostic that reduces inappropriate use," he says.

One of the most common tasks that doctors face is to diagnose if a disease is caused by a bacterium or a virus, but this is extremely difficult. The symptoms overlap. "The types of diagnostic tests traditionally used by doctors are time consuming and complex," says Cbadandra Kelly-Cirino, director of emerging threats at the Geneva-based Foundation for Innovative Diagnostics. "Most doctors err on the side of caution and administer antibiotics, even though the patient may be infected with the virus. or not.

In 2014, with the aim of developing new accessible diagnostic tests, the UK government launched the £ 8 million Longitude Award, which today controls 83 teams in 14 countries. "Some projects are really innovative," says Daniel Berman of Nesta, who leads the team of judges. An Australian group is using AI to examine trends in blood tests to predict sepsis. A team in Pune, India, has developed an ingenious credit card size test called USense to look for urinary tract infections. "You put in a urine sample and that tells you which of the four antibiotics would be likely," says Berman. The results take 60 minutes. If successful, the USense test could help prevent cases such as Debbie Forsyth's, in which a faster diagnosis could have prevented sepsis.

Reducing antibiotic resistance will require such international efforts. About 90% of the expected deaths due to AMR will occur in Africa and Asia – countries where antibiotic overuse and resistant infections are highest. When AMR was published in 2016, O'Neill was encouraged by the international response. But since then, Brexit and the Trump administration have removed AMR from the news agenda. And despite enthusiastic rhetoric, pharmaceutical companies continue to trample water.

"I sometimes think that pharmaceutical executives say," We will wait for the crisis to turn into a real crisis, "O'Neill said.