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



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TThe first antibiotic that did not work for Debby Forsyth was trimethoprim. In March 2016, Forsyth, a genius primary care advisor from Morpeth, Northumberland, received urinary tract infections. UTI is common: more than 150 million people worldwide are contracted annually. So when Forsyth saw his GP, they prescribed normal treatment: a three-day course of antibiotics. When she passed out a few weeks later, she again saw her doctor, who again prescribed trimethoprim.

Three days after that, Forsyth's husband, Pete, returned home to find a woman lying on the couch and shaking without being able to call for help. He was taken to A & E. It was surrounded by another antibiotic, gentamicin, and treated for sepsis, which is a complication of an infection that can be fatal if it is not healed quickly. Gentamicin also did not work. Doctors sent Forsyth blood for testing, but such tests may take several days: bacteria should be grown in cultures, and then tested against several antibiotics to find appropriate treatment. Five days after she was admitted to the hospital, Forsyth was diagnosed with multiple drug resistance E coliand using ertapenem, one of the so-called antibiotics in extreme emergency.

It worked. But the damage caused by the episode has remained and lives in constant fear of the repetition of the infection. Six months after its collapse, she developed another UTI, which again caused hospitalization. "I had to accept that I would not go back to where I was," she says. "My daughter and son said that you felt like you lost your mother, because I was not the one I used to be." But Forsyth was lucky. Sepses are currently killing more people in the United Kingdom than lung cancer, but the number is rising as more of us develop antibodies that are immune to antibiotics.

Antimicrobial resistance (AMR) – the process of bacteria (and yeasts and viruses) that develop the defense mechanisms against drugs that we use for treatment – is progressing so quickly that the United Nations has called it a "global health emergency". At least 2 million Americans suffer from drug-resistant infections each year. The so-called "superbugs" spread rapidly, partly because some bacteria are capable of borrowing the genes of resistance of adjacent species through a process called horizontal gene transfer. In 2013, researchers in China discovered E coli containing mcr-1, a colic-resistant gene, the latest antibiotic that has been considered to be too toxic for human use until recently. Colistin resistant infections are now detected in at least 30 countries.

"In India and Pakistan, Bangladesh, China and the countries of South America, the problem of resistance is already endemic," says Colin Garner, CEO of Antibiotic Research UK. In May 2016, the United Kingdom Government An overview of antimicrobial resistance predict that by 2050, antibiotic-resistant infections could kill 10 million people a year – more than all together.

"We have a good chance to get to the point where there are not many people [effective] antibiotics, "said Daniel Berman, head of the global health team at Nesta. It's hard to imagine a threat. A world without antibiotics means a return to the time without organs transplantation, without replacing the hip, without many routine operations. This would mean that millions of women die at birth; disable a lot of cancer treatment, including chemotherapy; and even the smallest wound is potentially fatal. As Berman told me: "Those who closely follow us are actually quite scared."

Bacteria are everywhere: in our bodies, in the air, in the soil, they coat every surface in their sextillion. Many bacteria produce antibiotic compounds – exactly how many of them we do not know – probably as a weapon in the microscopic battle for resources among the various strains of bacteria that have been happening for billions of years. Because bacteria reproduce so quickly, they can develop with surprising speed. The introduction of bacteria into a sufficiently weak antibiotic concentration and resistance can occur within a few days. Resistance to penicillin was first documented in 1940, the year before the first use in humans. (Often the misconception is that people can become resistant to antibiotics. No – bacteria do not.)

"Antibiotics are only present for the past 70 or 80 years. Bugs were on this planet for 3 billion years. And so they developed all kinds of survival mechanisms, "says Garner.

I bring hope: Glory Epstein, one of the discoverers of teixobactin.



I bring hope: Glory Epstein, one of the discoverers of teixobactin. Photo: Mary Knox Merrill

The problem is that antibiotics are nowadays everywhere. Every third of us is prescribed a course of antibiotics every year – one fifth of them unnecessarily, according to public health England. For many decades, many farmers have routinely injected livestock with antibiotics, which helped them to feed them to prevent infection (this practice is now banned in the EU, the US and Canada.) "Our generation is under stress from the effects of antibiotics," says Jim O & # 39; Neill, economist for government review. "The problem is that we use them for things that you do not need."

In the first decades of using antibiotics resistance was not a serious problem – you would only find a new medicine. When penicillin revolutionized medical care at the battlefields of the Second World War, the pharmaceutical industry began with the golden age of antibiotic discovery. The companies have included researchers, missionaries and travelers from all over the world in order to attract soil samples in hunting for new compounds. Streptomycin was detected in a field in New Jersey; vancomycin, jungle Bornea; cephalosporins from the sewage in Sardinia.

But the golden era was short-lived. New discoveries slowed down. Antibiotic compounds are common in nature, but those who can kill bacteria without harming humans are not. Soon, large pharmaceutical companies began to cut funding for their antibiotic research departments before closing them completely.

"The fact is that the private sector does not have enough investment to support new research and development," says Tim Jinks, head of the drug resistance program at Wellcome Trust. The problem is a simple economy: at best, antibiotics would be cheap, but they would be used as little as possible. This is not a big business proposal. Considering that resistance to antibiotics may occur one year after the introduction of a new class, the new antibiotic could have an effective lifespan of 10-15 years – hardly enough to pay for developing years. "We simply do not add numbers," he says.

There is still hope. In early 2015, researchers at Northeastern University in Massachusetts announced that they discovered a new class of antibiotics in the Maine area. It is called teixobactin, it is produced by a newly discovered bacterium, Eleftheria terraeand effectively against drug-resistant infections. Teixobactin was discovered by Slava Epstein and Kim Lewis using iChip, an ingenious USB chip device designed to overcome a problem that has been hit by biologists for decades: there are 1 billion bacteria in nature, only 1% of the species will grow in Petri. "We came to a simple gadget," says Lewis. "Take the bacteria out of the earth, sandwich between the two semi-permeable membranes and essentially outgrow the bacteria." So far, the pair has identified about 80,000 previously untreated strains with the device and isolated several stimulating new antibiotics.

Teixobactin is particularly promising for a simple reason: to date, no bacteria has been able to develop resistance to it. "When we published the document four years ago, many of my colleagues wrote me emails with the words" Send me the teixobactin and I'll send you back resistant mutants, "says Lewis. "I'm still waiting."

Ishwar Singh remembers the moment he heard about teixobactin: "It was January 7, 2015, on the BBC," he says. Singh was a reader at the University of Lincoln College of Pharmacy and specializes in the development of new medicines. The news inspired him. "Most antibiotics target protein. Teixobactin acts on the lipid – the wall of the cell wall, "explains. Attacks in several ways simultaneously, which makes it so far at least – impossible. Singh with a long stress swing with his head. "Nature built such a beautiful molecule."

Dr. Ishwar Singh University of Lincoln, Green Lane, Lincoln



"Nature has built such a beautiful molecule": Ishwar Singh of the University of Lincoln. Photo: Electric egg

Today, Singh leads one of several teams around the world who develop teixobactin. I meet him in the wet morning of January in his lab, where he wears frameless glasses and an expression of enthusiastic optimism. On one laboratory bench, Singh sketched the chemical structure of teixobactin in multi-colored tablets. Postdoctoral researchers mix, test samples for purity. A doctor holds a fine vial containing the width of fine white powders. "It's teixobactin," says Singh.

In the beginning, coping with such a small amount proved to be demanding. Then, in March of last year, Singh's team made a significant breakthrough: they replaced the heavily-produced amino acid with another, cheap available alternative. "There was not much to lose because people already said it would not work," he says. However, tests have shown that it has been effective in infecting mice. Singh estimates that the new structure has reduced production costs by 200,000 times.

However, Teixobactin is still a long time before testing in humans. If we put it on the market, it can take a decade or more, if it works at all. In addition, other new drugs are available: zoliflodacin, intended to treat multiple drug resistance Neisseria gonorrhea, is currently in the testing of three phases. In 2016, triggered by the rising crisis, the United States, the United Kingdom and charities, including Wellcome Trust, launched the CARB-X initiative to offer US $ 500 million to finance promising new antibiotics. Thanks to techniques such as fast gene sequencing and metagenomics that are looking for promising DNA in the environment, they are then cloned into new bacteria – scientists have recently discovered many promising new compounds, including one in the human nose. "Things are going really well, which is good," says Lewis. "But it's a small drop."

Given the urgency of the problem, others are more pragmatic approaches. One of the most promising is perhaps the simplest: giving more than one medicine to patients at a time. "Everything we use for conventional infection is monotherapy," explains Anthony Coates, professor of medical microbiology at St. George's Hospital in Tooting, London. In contrast, combined treatment using more than one supplementary medicine is standard in many other areas. "Aids is one, oncology is the other," he says. "Why do not we do this with conventional bacteria?"

I meet him at his home in London. He has quiet, thoughtful behavior, which makes his concern even more worrying. "AMR is a catastrophe," he says. "This deterioration is happening faster than I imagined."

Coates' specialty is in so-called anti-antibiotic resistance buffers – compounds that can, in combination, re-enable bacteria resistant to drugs. In 2002 he founded Helperby Therapeutics for the development of combined medicines; more are in clinical trials. "Let's check thousands of combinations," he says. Until recently, the work was slow and stressful, done manually, but the advancement in robotics and AI now allows most of this to be automated, which has enabled more complex combinations.

Precisely because of this, combination therapy is not always clear. "We understand a couple of dice: you have a bug, you break it in one antibiotic, and then another antibiotic is allowed," says Coates. "When you participate in three, it's more complicated. Four and five: very complex. "But how combinations of work are not as important as the fact that they work.

One of the benefits of combination therapy is that many of the medicines Helperby has reviewed has already been done with the extensive clinical trials that they needed before they could be administered to patients – "probably millions of people" – so the probability, that the drugs will not cease testing in humans, are lower.

Only new drugs will not solve the problem of resistance. "Yes, it's important to get new drugs, but it only helps to solve this problem for the second generation," says O & # 39; Neill. What caused the MRSA epidemic under control was not a cure but an improved hospital hygiene: washing hands. Neill's greatest wish is not even treatment. "If they told me," You can only have one thing, "it would be the most advanced diagnostic tool to reduce inappropriate use," she says.

Diagnosing a disease caused by bacteria or a virus is one of the most common tasks that doctors face, but it is very difficult. Symptoms overlap. "Types of diagnostic tests traditionally used by doctors require a lot of time and are complicated," explains Cassandra Kelly-Cirino, director of Emerging Threats at the Foundation for Innovative New Diagnostics from Geneva. "Most doctors will make a mistake on the side of the pacemaker and give antibiotics, although the patient might actually have a virus." If patients feel better, it is often easier (and cheaper) to regulate the course of penicillin, if necessary or not.

In 2014, the United Kingdom Government, in order to develop new, accessible diagnostic tests, introduced a $ 8 million lending prize, which today monitors 83 teams in 14 countries. "Some projects are truly innovative," says Nesta Daniel Berman, who heads a team of judges. The Australian group uses an AI to examine samples in blood tests to predict sepsis. A team from Pune, India, developed an original credit card test, called USense, to test the UTI. "Insert a sample of urine and tells you which of the four antibiotics would be susceptible," says Berman. The results last 60 minutes. If successful, the USense test could prevent cases such as Debby Forsyth's, in which a faster diagnosis could prevent sepsis.

Opening the resistance to antibiotics will require such international efforts. Approximately 90% of predicted AMR deaths will occur in Africa and Asia – countries where antibiotics are excessive and resistant to infections. When the AMR review was published in 2016, O & # 39; Neill prompted an international response. But from then on, Brexit and Trump's administration have ruined the AMR. And despite the enthusiastic rhetoric, pharmaceutical companies continue to go into the water.

"Sometimes I think the CEOs of pharmaceutical companies say that we" just wait for it to become a real crisis, "says O & # 39; Neill.

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