Penicillin and other antibiotics have saved countless lives. However, the age of these miraculous drugs seems to be coming to an end. Deaths from drug-resistant microbes will increase from the current 700,000 per year to 10 million by 2025. Then they will outstrip cancer, heart disease and diabetes in their harmful effects.
In January 2019, Columbia University reported that four patients at its Irving Medical Center in New York were suffering from an unusual type of E. coli. While this news largely went unnoticed by the media, it attracted the attention of infectious disease experts. E. coli is a fairly common bacterium and is harmless if found in the stomach where it usually lives, but can become deadly in the wrong places, such as in lettuce, in ground beef, or in our circulatory system. In the event that antibiotics are helpless in the fight against E. coli, half of the patients die within two weeks.
This is why Columbia University's report on E. coli caused such alarm. For some infected patients, the last resort lies with the antibiotic colistin, a toxic substance that can cause side effects and damage the kidneys and brain. The E. coli reported by Columbia University had a mutation in the MCR-1 gene, giving it the terrible property of being immune to colistin.
“We're trying to find a new antibiotic, but we can't find anything,” says Erica Shenoy, deputy director of infection control at Massachusetts General Hospital. "We can get patients with an infectious disease that we cannot fight."
Since 1942, when a miraculous experimental drug called penicillin was rushed to Boston Hospital, where it saved the lives of 13 victims of a nightclub shootout, medical scientists have discovered over 100 new antibiotics. We need all of them, but they are no longer enough. And the reason is not only E. coli. There are also species of Staphylococcus, Enterobacteriaceae, and Clostridium difficile that have been shown to be effective against antibiotics. One study found that deaths from antibiotic-resistant diseases quadrupled between 2007 and 2015. Recently, a resistant, resistant version of the fungus Candida auris was discovered in hospitals in New York and Chicago.which caused the death of half of the infected patients.
“The US Centers for Disease Control and Prevention reports that two million people a year in America suffer from bacteria or fungi that are resistant to the main antibiotics, and that 23,000 people die from them. “And this is probably a significant underestimation,” says Karen Hoffmann, head of the Association for Professionals in Infection Control and Epidemiology. “We don't have a good system for keeping track of multi-drug resistant organisms, so we can't say for sure.” Studies have shown that the annual cost of serving patients with this kind of diseases by the American healthcare system exceeds $ 3 billion.
Bacteria under a microscope.
Apparently, this gloomy trend will continue. World Health Organization experts say that worldwide deaths from drug-resistant microbes will increase from the current 700,000 a year to 10 million by 2025. By this time, having become the main cause of death of people, they will outstrip cancer, heart disease and diabetes in their destructive effects. Before antibiotics were discovered, a small cut, tooth decay, or routine surgery could have caused deadly bacterial contamination. Penicillin, the "miracle cure", and other antibiotics have saved countless lives in recent years. However, the age of these miraculous drugs seems to be coming to an end.
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Scientists are trying to identify and isolate bacteria that are already refractory to existing drugs in the hopes that large-scale disease outbreaks can be avoided. They are trying to reduce the use of antibiotics to slow the emergence of resistant bacteria. But all this is too little, and it is done too late. Such a strategy will only allow us to gain a certain amount of time. The oldest and weakest patients in hospitals are currently the most vulnerable category, but risks of this kind continue to spread. “We see healthy young people with urinary tract or skin infections and we don't have the drugs to treat them,” says Helen Boucher.an infectious disease specialist at Tufts Medical Center in Boston. “We probably won't be able to do organ transplants, and we won't even be able to do routine surgeries like joint replacement. This should be of concern to all of us."
Medical experts are pinning their hopes on entirely new strategies for treating infectious diseases. They are looking for new ways to destroy bacteria in exotic places - in viruses, fish slime and even on other planets. They leverage developments in genomics as well as other fields and offer new technologies to eliminate bacteria and limit their spread. In addition, they are further researching therapies in hospitals and elsewhere where bacteria are spread, using more holistic strategies to fight bacteria in our bodies, as well as in our hospitals and doctors' offices.
Alternative options seem promising, but their implementation is still far away. It is not yet clear if we will be able to devise any new means before superbugs, like the zombie army at the gates, destroy our defenses.
“We need to invest huge amounts of money in developing other approaches,” says Margaret Riley, a drug-resistant bacteria specialist at the University of Massachusetts. "And it was necessary to start doing this 15 years ago."
New germ hunters
Part of the problem with drug resistance is that microbes are evolving into new species at an alarming rate. If it takes a person 15 years or more to be able to reproduce, microbes such as E. coli reproduce every 20 minutes. Over the course of several years, they are able to go through a period of evolutionary development, whereas it would take a person millions of years, and such changes include the possibility of obtaining such genetic characteristics that can withstand the effects of drugs. The person taking antibiotics is the perfect laboratory for the production of drug-resistant microbes. “Research showsthat when a new drug is introduced, the first microbes that are resistant to it are formed within a year,”says Shenoy of Massachusetts General Hospital.
And in the pharmaceutical field, there is almost nothing to replace antibiotics, which no longer act in an appropriate way on bacteria. In addition, it takes about $ 2 billion and about 10 years to develop a new antibiotic - with very little hope that the result will be a super drug that justifies such an investment. “The trick to owning a new antibiotic is to use it as many times and in as short a time as possible,” said Jonathan Zenilman, head of the infectious disease department at Johns Hopkins University Bayview Medical Center in Baltimore. Johns Hopkins Bayview Medical Center). "What could force a pharmaceutical company to develop a drug for such a market?" he asks.
Medical researchers are currently looking for other approaches. One of them is to involve biologists interested in using evolutionary theory to fight bacteria. In the 1990s, under Riley's leadership at Harvard and Yale, research began on how viruses kill bacteria and bacteria destroy each other. In 2000, one of her colleagues constantly asked her if her work had anything to do with human health. “I never thought about it,” she says. "But suddenly everything became clear to me, and I was seized by this question."
Since then, Riley has spent two decades trying to apply a virus warfare strategy to solving the problem of persistent infectious diseases in humans. Viruses called phages, which are essentially part of the genetic material in a protective protein sheath, destroy the bacterial cell walls and hijack its genetic machinery, thus turning the bacterium itself into a factory to produce more viruses. Riley is also studying how bacteria sometimes kill other bacteria in the fight for food. In doing so, the bacteria colony sometimes pushes competitors out with a toxic protein they produce called bacteriocins.
Riley's goal is not only to kill the harmful bacteria, but also to protect the beneficial ones. Of the roughly 400 trillion bacteria that inhabit every one of our bodies, she says, the vast majority are beneficial or harmless, and only 10,000 percent of them are potentially harmful. Wide-spectrum antibiotics such as penicillin, ciprofloxacin and tetracycline, widely used by doctors as directed by doctors, cannot distinguish between good and bad bacteria - they destroy them all indiscriminately. As a result, these treatments not only promote the emergence of resistant bacteria, but also cause problems for the patient.
“Using antibiotics is like dropping a hydrogen bomb on an infection,” Riley says. "You kill 50% or more of the total bacteria in your body, and as a result, the lack of good bacteria can lead to obesity, depression, allergies and other problems." On the other hand, bacteriophages and bacteriocides are theoretically capable of destroying a colony of infectious bacteria in a patient, all without harming normal flora or creating fertile soil for the formation of resistant bacteria.
ImmuCell, a biotech company in Portland, Maine, has developed bacteriocin, which treats cows for mastitis, a disease that costs the dairy industry $ 2 billion annually. Riley says her lab and others like her can make bacteriophages and bacteriocins target any human microbial contamination without the risk of increased resistance. “This is a stable and durable destruction mechanism that appeared 2 billion years ago,” she says.
Several clinical trials of bacteriophage therapy have already been successfully carried out in Poland, Georgia and Bangladesh. In the West, successful trials are being carried out on the use of bacteriophages in the treatment of leg ulcers. While no trials are underway to treat more serious diseases, the successful use of bacteriophages in the treatment of a multidrug-resistant patient in California in 2017 under the FDA's emergency regulations has led to more scientists in the United States are trying to develop bacteriocyte therapies. Some of them in the next few years may advance further in such studies,including in the treatment of multi-drug resistant tuberculosis and other lung infections in patients with cystic fibrosis, Riley notes. Research on the use of bacteriophages is still far behind. The United States government has pledged $ 2 billion to develop such alternative methods, but according to Riley, "these funds are far from sufficient."
Cancer experts are actively studying drugs that can strengthen the immune system, and this type of immunotherapy can help a weakened patient's body fight resistant bacteria in his body. Researchers have succeeded in producing human antibodies in cows and other mammals that can be injected into a patient's body. The Brigham Hospital and Women's Hospital, affiliated with Harvard University, Boston, and Women's Hospital, as a result of emergency work, reported the introduction of a combination of antibodies and antibiotics to save a patient with a resistant infection, but the results of treatment have not yet been released. Otherwise, we can say that little work is being done using such approaches in the treatment of infected patients. Researchers are also trying to develop vaccines against resistant staphylococcal infections and other resistant bacteria, but so far this is only about research. “This kind of antibiotic-free treatment is still in the early stages of research,” said David Banach, head of infectious disease control at UConn Health medical center in Farmington, Connecticut. But we must keep looking for new approaches. "Head of Infectious Disease Control at UConn Health medical center in Farmington, Connecticut "But we must keep looking for new approaches."Head of Infectious Disease Control at UConn Health medical center in Farmington, Connecticut "But we must keep looking for new approaches."
Given the incredible urgency of this problem, the question arises: why promising solutions have been tested for so long and remain unavailable for so long? Because little money is being invested in these developments, says Bushehr of Taft Medical Center. The state spends billions on research, but there is no private investment to turn research results into manufactured drugs and devices. According to Busher, pharmaceutical companies have little chance of making a profit from producing drugs that are unlikely to be used by millions of people. It is equally unlikely that the price will rise to tens of thousands of dollars per dose. “This economic model doesn't work,” she says.
Bacteria management
Although antibiotics are actually miraculous drugs, our current problems are partly due to the fact that medicine has placed too much emphasis on them. Doctors prescribe them for ear infections, sore throat, and urinary tract infection. Surgeons use them to prevent postoperative infections. Bacteria can develop resistance, and antibiotics make sense as part of a holistic approach to control bacterial proliferation and to treat infections. Antibiotics are slowly losing their effectiveness, which is why medical experts emphasize the need for comprehensive strategies to keep bacteria under control.
Faster identification and response to emerging disease outbreaks, as well as special precautions in the targeted use of antibiotics, help to slow down or prevent this process. New tests in development will enable healthcare professionals to quickly and cheaply identify the genes of any bacteria found in or near a patient. “We are not able to conduct molecular research on every patient who comes to us. It would be trying to find a needle in a haystack, says Shenoy. “But if we can do the research on high-risk patients quickly enough, then we can take action.” Such an option would undoubtedly be an improvement over the standard bacterial disease outbreak identification technique developed 150 years ago.
In addition, infectious disease specialists are focusing on containing resistant bacteria when they appear in hospitals, rather than allowing them to spread to patients. Approximately 5% of all patients in hospitals in the United States contract a nosocomial infection - that is, directly in the hospital itself. It is not hard to see why this is happening. Hospitals are a large gathering of sick people with weakened immune systems and various wounds and lesions that are treated with fingers and medical instruments, and then those fingers and instruments are used to serve other patients.
An aging population and new procedures make hospital patients even more vulnerable. Zenilman of Johns Hopkins University Medical Center conducted an informal study and found that more than half of all patients had some type of implant, which is a common source of infection. “Patients in hospitals today are more sick as a group than ever before,” he notes. "Research shows that, on average, hospitals fail to take action in about half of the cases," says Hoffman of the Association for Infection Control and Epidemiology Professionals. "This is our biggest problem."
Hospitals are starting to change their practice. Many now use robots in the form of trash cans to disinfect walls with ultraviolet light (the wards should be empty at this time, since such light is harmful to humans). At Riverside Medical Center, south of Chicago, two robots made by Xenex disinfect more than 30 wards a day.
It would be easier to keep hospitals clean if bacteria were not able to adhere to surfaces such as tabletops and clothing. Melissa Reynolds, a biomedical engineer at Colorado State University, is developing materials that are resistant to bacteria. Health care workers' clothing and other materials and surfaces used in hospitals would not need to be disinfected as often if bacteria did not accumulate. Fighting bacteria is a random direction in Reynolds' work. She studied how to avoid clotting in the meshes used by surgeons to keep a patient's arteries open. The use of a special coating in grids, consisting of copper nanocrystals, seems to beprevents blood cells from sticking to the surface. She also drew attention to the fact that bacteria are not able to adhere to the nanocrystalline coating. And at some point one of the students in her laboratory exclaimed “Eureka! Why not dip a cotton cloth into a nanocrystalline solution so that bacteria cannot stay on the cloth? " “After that, we discovered some new materials with antibiotic properties,” Reynolds said. "It brought us to a new direction in our work."so that bacteria can't stay on the tissue? " “After that, we discovered some new materials with antibiotic properties,” Reynolds said. "It brought us to a new direction in our work."so that bacteria can't stay on the tissue? " “After that, we discovered some new materials with antibiotic properties,” Reynolds said. "It brought us to a new direction in our work."
The idea of a relatively bacteria-resistant tissue has already passed a series of tests. “Time after time, we exposed the treated tissue to all sorts of bacteria, and after that we could not find any bacteria on it,” she says. "We are still trying to figure out this mechanism, but we know that this method is effective with a wide variety of types of bacteria." She is already working with a major medical device company to prove that nanocrystals can be incorporated into a manufacturing process at little additional cost. She is currently exploring ways to use these crystals in other hospital materials, including stainless steel, paints and plastics. Materials treated in this way will be protected from bacteria for much longer,than traditional hospital surfaces treated with conventional disinfectants, she notes.
Lasers are another potential bacteria-fighting tool. Mohamed Seleem of Purdue University and his colleagues are trying to find a way to quickly identify infectious bacteria in blood samples by exposing them to laser beams of different colors. In the process, they found that certain drug-resistant bacteria were able to change their color from gold to white within just a few seconds after being briefly exposed to a blue laser beam. Some of these "photobleached" bacteria died, while others were so weak that they lost their ability to resist the effects of conventional antibiotics. It turned out that blue light attacks the pigments in the outer membrane of bacteria. “It only works on a certain pigment,” says Selim."Therefore, no other cells are affected."
Selim and his colleagues are trying to find ways to tune the color of the laser to target certain resistant bacteria. If his work is successful, healthcare workers can use lasers no larger than a standard flashlight to safely destroy harmful bacteria on a patient's skin and disinfect doctors' offices. The beam can also be used to treat the skin and clothing of health workers themselves to prevent them from spreading the infection. His colleagues are currently preparing to conduct clinical trials.
Selim also believes that this light can be used for serious and dangerous resistant blood infections. In this case, the patient can be connected to a heart-lung machine and the blood can be treated with such a beam as it passes through the machine. “Basically, you take the patient's blood, sterilize it and return it to the patient,” he says.
Slow down the development of superbugs
Although the pharmaceutical industry has largely abandoned the production of antibiotics, researchers still hope to find new types of antibiotics. The antibiotic revolution began in 1928 when Alexander Fleming returned from vacation to his London laboratory and discovered a strange-looking mold that had formed in a ditch he left by the window. Since then, researchers have been trying to survey every corner of nature in the hope of finding new killer bacteria. New substances that may be deadly to resistant bacteria - but harmless to humans - are recent reports suggesting insects, algae, juvenile fish mucus, arsenic-rich mud in Ireland and even Martian soil. One group of researchers from Leiden University in Holland is trying to create an artificial bacterium in the hope thatthat on its basis it will be possible to obtain a new antibiotic.
In addition, doctors are trying to make the most of existing antibiotics by slowing down the emergence of new resistant species. This requires reducing the overuse of antibiotics, which gives superbugs an incentive for evolutionary development. Such action must become international, as resistant bacteria often travel from one part of the world to another.
Developing countries are especially prone to bacterial threats, which then travel to the United States, says Yukon's Banak. Studies have found that most of the world's antibiotics are already distributed over-the-counter by local pharmacies, leading to a 65 percent increase in antibiotic use between 2000 and 2015. The resulting resistant bacteria easily migrate around the world in the stomachs of millions of travelers. “The impact of the overuse of antibiotics in these countries, as well as the living conditions there and the environment, are conducive to the worldwide spread of resistant organisms,” he stresses.
David H. Freedman