Antibiotic resistance modern approaches and ways to overcome. WHO Global Strategy to Contain Antimicrobial Resistance. About mechanisms: continuing the theme

According to historical sources, many thousands of years ago, our ancestors, faced with diseases caused by microorganisms, fought them with available means. Over time, mankind began to understand why certain drugs used since ancient times can affect certain diseases, and learned to invent new drugs. Now the amount of funds used to combat pathogens has reached an especially large scale, compared even with the recent past. Let's take a look at how people throughout history, sometimes without knowing it, used antibiotics, and how, with the accumulation of knowledge, they use them now.

A special project on humanity's fight against pathogenic bacteria, the emergence of antibiotic resistance and a new era in antimicrobial therapy.

The sponsor of the special project is a developer of new highly effective binary antimicrobial drugs.

Bacteria appeared on our planet, according to various estimates, approximately 3.5–4 billion years ago, long before eukaryotes. Bacteria, like all living beings, interacted with each other, competed and fought. We can't say for sure if they were already using antibiotics to beat other prokaryotes in the fight for a better environment or nutrients. But there is evidence for genes encoding resistance to beta-lactam, tetracycline, and glycopeptide antibiotics in the DNA of bacteria that were in a 30,000-year-old ancient permafrost.

A little less than a hundred years have passed since the moment that is considered to be the official discovery of antibiotics, but the problem of creating new antimicrobial drugs and using those already known, subject to rapidly emerging resistance to them, has been worrying mankind for more than fifty years. Not without reason in his Nobel speech, the discoverer of penicillin Alexander Fleming warned that the use of antibiotics should be taken seriously.

Just as the discovery of antibiotics by mankind is delayed by several billion years from their initial appearance in bacteria, the history of human use of antibiotics began long before their official discovery. And this is not about the predecessors of Alexander Fleming, who lived in the 19th century, but about very distant times.

The use of antibiotics in antiquity

Even in ancient Egypt, moldy bread was used to disinfect cuts (video 1). Bread with molds was also used for medicinal purposes in other countries and, apparently, in general in many ancient civilizations. For example, in ancient Serbia, China and India, it was applied to wounds to prevent the development of infections. Apparently, the inhabitants of these countries independently came to the conclusion about the healing properties of the mold and used it to treat wounds and inflammatory processes on the skin. The ancient Egyptians applied crusts of moldy wheat bread to pustules on the scalp and believed that using these remedies would help propitiate the spirits or gods responsible for illness and suffering.

Video 1. Causes of mold, its harm and benefits, as well as medical applications and prospects for future use

The inhabitants of Ancient Egypt used not only moldy bread, but also self-made ointments to treat wounds. There is information that around 1550 BC. they prepared a mixture of lard and honey, which was applied to wounds and tied with a special cloth. Such ointments had some antibacterial effect, including due to the hydrogen peroxide contained in honey,. The Egyptians were not pioneers in the use of honey - the first mention of its healing properties is considered to be an entry on a Sumerian tablet dating from 2100-2000 BC. BC, where it is said that honey can be used as medicine and ointment. And Aristotle also noted that honey is good for healing wounds.

In the process of studying the bones of the mummies of ancient Nubians who lived on the territory of modern Sudan, scientists found a large concentration of tetracycline in them. The age of the mummies was approximately 2500 years, and, most likely, high concentrations of the antibiotic in the bones could not have appeared by chance. Even in the remains of a four-year-old child, its number was very high. Scientists suggest that these Nubians consumed tetracycline for a long time. It is most likely that the source was bacteria. Streptomyces or other actinomycetes contained in the grains of plants from which the ancient Nubians made beer.

Plants have also been used by people around the world to fight infections. It is difficult to understand exactly when some of them began to be used, due to the lack of written or other material evidence. Some plants were used because a person learned through trial and error about their anti-inflammatory properties. Other plants have been used in cooking, and along with their taste properties, they also had antimicrobial effects.

This is the case with onions and garlic. These plants have long been used in cooking and medicine. The antimicrobial properties of garlic were known back in China and India. And not so long ago, scientists found that traditional medicine used garlic for a reason - its extracts depress Bacillus subtilis, Escherichia coli and Klebsiella pneumonia .

Since ancient times, Schisandra chinensis has been used in Korea to treat gastrointestinal infections caused by salmonella. Schisandra chinensis. Already today, after testing the effect of its extract on this bacterium, it turned out that lemongrass really has an antibacterial effect. Or, for example, spices that are widely used around the world were tested for the presence of antibacterial substances. It turned out that oregano, cloves, rosemary, celery and sage inhibit pathogens such as Staphylococcus aureus, Pseudomonas fluorescens and Listeria innocua. On the territory of Eurasia, peoples often harvested berries and, of course, used them, including in treatment. Scientific studies have confirmed that some berries have antimicrobial activity. Phenols, especially ellagitannins found in cloudberries and raspberries, inhibit the growth of intestinal pathogens.

Bacteria as a weapon

Diseases caused by pathogenic microorganisms have long been used to harm the enemy at minimal cost.

At first, Fleming's discovery was not used to treat patients and continued its life exclusively behind the doors of the laboratory. In addition, as Fleming's contemporaries reported, he was not a good speaker and could not convince the public of the usefulness and importance of penicillin. The second birth of this antibiotic can be called its rediscovery by British scientists Ernst Cheyne and Howard Flory in 1940-1941.

Penicillin was also used in the USSR, and if a not particularly productive strain was used in the UK, then the Soviet microbiologist Zinaida Ermolyeva discovered one in 1942 and even managed to establish the production of an antibiotic in wartime conditions. The most active strain was Penicillium crustosum, and therefore at first the isolated antibiotic was called penicillin-crustosin. It was used on one of the fronts during the Great Patriotic War for the prevention of postoperative complications and the treatment of wounds.

Zinaida Ermolyeva wrote a short brochure in which she talked about how penicillin-crustosin was discovered in the USSR and how other antibiotics were searched for: " Biologically active substances".

In Europe, penicillin was also used to treat the military, and after this antibiotic began to be used in medicine, it remained the exclusive privilege of the military. But after a fire on November 28, 1942, in a Boston nightclub, penicillin began to be used to treat civilian patients. All the victims had burns of varying degrees of complexity, and at that time such patients often died from bacterial infections caused, for example, by staphylococci. Merck & Co. sent penicillin to the hospitals where the victims of this fire were kept, and the success of the treatment put penicillin in the public eye. By 1946 it had become widely used in clinical practice.

Penicillin remained available to the public until the mid-1950s. Naturally, being in uncontrolled access, this antibiotic was often used inappropriately. There are even examples of patients who believed that penicillin was a miracle cure for all human diseases, and even used it to “treat” something that by its nature is not capable of succumbing to it. But in 1946, in one of the American hospitals, they noticed that 14% of strains of staphylococcus taken from sick patients were resistant to penicillin. And in the late 1940s, the same hospital reported that the percentage of resistant strains had risen to 59%. It is interesting to note that the first information that resistance to penicillin occurs appeared in 1940 - even before the antibiotic began to be actively used.

Before the discovery of penicillin in 1928, there were, of course, discoveries of other antibiotics. At the turn of the 19th–20th centuries, it was noticed that the blue pigment of bacteria Bacillus pyocyaneus able to kill many pathogenic bacteria, such as cholera vibrio, staphylococci, streptococci, pneumococci. It was named pyocyanase, but the discovery did not form the basis for the development of the drug because the substance was toxic and unstable.

The first commercially available antibiotic was Prontosil, which was developed by the German bacteriologist Gerhard Domagk in the 1930s. There is documentary evidence that the first cured person was his own daughter, who had long suffered from a disease caused by streptococci. As a result of treatment, she recovered in just a few days. Sulfanilamide preparations, which include Prontosil, were widely used during the Second World War by the countries of the anti-Hitler coalition to prevent the development of infections.

Shortly after the discovery of penicillin, in 1943, Albert Schatz, a young employee in the laboratory of Selman Waksman, isolated from soil bacteria Streptomyces griseus substance with antimicrobial activity. This antibiotic, called streptomycin, proved to be active against many common infections of the time, including tuberculosis and plague.

And yet, until about the 1970s, no one seriously thought about the development of antibiotic resistance. Then two cases of gonorrhea and bacterial meningitis were seen, when a bacterium resistant to treatment with penicillin or penicillin antibiotics caused the death of the patient. These events marked the moment when decades of successful treatment of diseases were over.

It must be understood that bacteria are living systems, therefore they are changeable and, over time, are able to develop resistance to any antibacterial drug (Fig. 2). For example, bacteria could not develop resistance to linezolid for 50 years, but still managed to adapt and live in its presence. The probability of developing antibiotic resistance in one generation of bacteria is 1:100 million. They adapt to the action of antibiotics in different ways. This may be a strengthening of the cell wall, which, for example, uses Burkholderia multivorans that causes pneumonia in immunocompromised people. Some bacteria such as Campylobacter jejuni, which causes enterocolitis, very effectively “pump out” antibiotics from cells using specialized protein pumps, and therefore the antibiotic does not have time to act.

We have already written in more detail about the methods and mechanisms of adaptation of microorganisms to antibiotics: Racing evolution, or why antibiotics stop working» . And on the website of the online education project Coursera there is a useful course on antibiotic resistance Antimicrobial resistance - theory and methods. It describes in sufficient detail about antibiotics, the mechanisms of resistance to them and the ways in which resistance spreads.

The first case of methicillin-resistant Staphylococcus aureus (MRSA) was recorded in the UK in 1961, and in the US a little later, in 1968. We will talk a little more about Staphylococcus aureus later, but in the context of the rate of development of resistance in it, it is worth noting that in 1958 the antibiotic vancomycin began to be used against this bacterium. He was able to work with those strains that did not succumb to the effects of methicillin. And until the end of the 1980s, it was believed that resistance to it should be developed for a longer time or not developed at all. However, in 1979 and 1983, after only a couple of decades, cases of resistance to vancomycin were also recorded in different parts of the world.

A similar trend was observed for other bacteria, and some were able to develop resistance in a year at all. But someone adapted a little more slowly, for example, in the 1980s, only 3-5% S. pneumonia were resistant to penicillin, and in 1998 - already 34%.

XXI century - "crisis of innovations"

Over the past 20 years, many large pharmaceutical companies - such as Pfizer, Eli Lilly and Company and Bristol-Myers Squibb - have reduced the number of developments or completely closed projects to create new antibiotics. This can be explained not only by the fact that it has become more difficult to find new substances (because everything that was easy to find has already been found), but also because there are other sought-after and more profitable areas, such as the creation of drugs for the treatment of cancer or depression.

However, from time to time, one or another team of scientists or a company announces that they have discovered a new antibiotic, and states that “here it will definitely defeat all bacteria / some bacteria / a certain strain and save the world.” After that, often nothing happens, and such statements cause only skepticism in the public. Indeed, in addition to testing the antibiotic on bacteria in a Petri dish, it is necessary to test the alleged substance on animals, and then on humans. It takes a lot of time, is fraught with many pitfalls, and usually at one of these phases, the opening of the “miraculous antibiotic” is replaced by a closure.

In order to find new antibiotics, various methods are used: both classical microbiology and newer ones - comparative genomics, molecular genetics, combinatorial chemistry, structural biology. Some suggest moving away from these "usual" methods and turning to the knowledge accumulated throughout human history. For example, in one of the books in the British Library, scientists noticed a recipe for a balm for eye infections, and they wondered what he was capable of now. The recipe dates back to the 10th century, so the question is - will it work or not? - was really intriguing. Scientists took exactly those ingredients that were indicated, mixed them in the right proportions and tested for methicillin-resistant Staphylococcus aureus (MRSA). To the surprise of the researchers, over 90% of the bacteria were killed by this balm. But it is important to note that such an effect was observed only when all the ingredients were used together.

Indeed, sometimes antibiotics of natural origin work no worse than modern ones, but their composition is so complex and depends on many factors that it is difficult to be sure of any particular result. Also, it is impossible to tell if the rate of resistance to them is slowing down or not. Therefore, they are not recommended to be used as a replacement for the main therapy, but as an addition under the strict supervision of doctors.

Resistance problems - examples of diseases

It is impossible to give a complete picture of the resistance of microorganisms to antibiotics, because this topic is multifaceted and, despite the somewhat subsided interest on the part of pharmaceutical companies, is being actively studied. Accordingly, information about more and more cases of antibiotic resistance appears very quickly. Therefore, we will limit ourselves to only a few examples in order to at least superficially show the picture of what is happening (Fig. 3).

Tuberculosis: a risk in the modern world

Tuberculosis is especially prevalent in Central Asia, Eastern Europe and Russia, and the fact that tuberculosis microbes ( Mycobacterium tuberculosis) resistance not only to certain antibiotics, but also to their combinations, should be cause for concern.

Due to reduced immunity, HIV patients often develop opportunistic infections caused by microorganisms that can normally be present in the human body without harm. One of them is tuberculosis, which is also noted as the main cause of death of HIV-positive patients worldwide. The prevalence of tuberculosis by regions of the world can be judged from statistics - in patients with HIV who have developed tuberculosis, if they live in Eastern Europe, the risk of dying is 4 times higher than if they lived in Western Europe or even Latin America. Of course, it is worth noting that this figure is influenced by the extent to which it is customary in the medical practice of the region to conduct tests for the susceptibility of patients to drugs. This allows antibiotics to be used only when needed.

WHO is also monitoring the situation with tuberculosis. In 2017, she released a report on tuberculosis survival and monitoring in Europe. There is a WHO strategy to eliminate tuberculosis, and therefore close attention is paid to regions with a high risk of contracting this disease.

Tuberculosis claimed the lives of such thinkers of the past as the German writer Franz Kafka and the Norwegian mathematician N.Kh. Abel. However, this disease is alarming both today and when trying to look into the future. Therefore, both at the public and state levels, it is worth listening to the WHO strategy and trying to reduce the risks of contracting tuberculosis.

The WHO report highlights that since 2000, fewer cases of TB infection have been recorded: between 2006 and 2015, the number of cases decreased by 5.4% per year, and in 2015 decreased by 3.3%. Nevertheless, despite this trend, WHO calls for attention to the problem of antibiotic resistance mycobacterium tuberculosis, and, using hygiene practices and constant monitoring of the population, to reduce the number of infections.

resistant gonorrhea

The extent of resistance in other bacteria

Approximately 50 years ago, strains of Staphylococcus aureus resistant to the antibiotic methicillin (MRSA) began to appear. Methicillin-resistant Staphylococcus aureus infections are associated with more deaths than methicillin-resistant Staphylococcus aureus (MSSA) infections. Most MRSA are also resistant to other antibiotics. Currently, they are common in Europe, and in Asia, and in both Americas, and in the Pacific region. These bacteria are more likely than others to become resistant to antibiotics and kill 12,000 people a year in the US. There is even a fact that in the US MRSA claims more lives per year than HIV / AIDS, Parkinson's disease, emphysema and homicides combined,.

Between 2005 and 2011, fewer cases of MRSA infection as a nosocomial infection began to be recorded. This is due to the fact that the observance of hygienic and sanitary standards has been taken under strict control in medical institutions. But in the general population, this trend, unfortunately, does not persist.

Enterococci resistant to the antibiotic vancomycin are a big problem. They are not as widespread on the planet, compared to MRSA, but in the United States about 66 thousand cases of infection are recorded every year. Enterococcus faecium and, less often, E. faecalis. They are the cause of a wide range of diseases and especially among patients in medical institutions, that is, they are the cause of hospital infections. When infected with enterococcus, about a third of cases occur in strains resistant to vancomycin.

Pneumococcus Streptococcus pneumoniae is the cause of bacterial pneumonia and meningitis. Most often, the disease develops in people over 65 years of age. The emergence of resistance complicates treatment and ultimately leads to 1.2 million cases and 7,000 deaths annually. Pneumococcus is resistant to amoxicillin and azithromycin. It has also developed resistance to less common antibiotics, and in 30% of cases it is resistant to one or more of the drugs used in the treatment. It should be noted that even if there is a small level of resistance to an antibiotic, this does not reduce the effectiveness of treatment with it. The use of the drug becomes useless if the number of resistant bacteria exceeds a certain threshold. For community-acquired pneumococcal infections, this threshold is 20–30%. There have been fewer cases of pneumococcal infections recently, because in 2010 a new version of the PCV13 vaccine was created that works against 13 strains. S. pneumoniae.

Pathways for the spread of resistance

An exemplary circuit is shown in Figure 4.

Close attention should be given not only to bacteria that are already developing or have developed resistance, but also to those that have not yet acquired resistance. Because over time, they can change and begin to cause more complex forms of diseases.

The attention to non-resistant bacteria can also be explained by the fact that, even if easily treatable, these bacteria play a role in the development of infections in immunocompromised patients - HIV-positive, undergoing chemotherapy, premature and postterm newborns, people after surgery and transplantation. And since there are a sufficient number of these cases -

• around 120,000 transplants were performed worldwide in 2014;
• in the US alone, 650,000 people undergo chemotherapy every year, but not everyone has the opportunity to use drugs to fight infections;
• in the USA, 1.1 million people are HIV-positive, in Russia - a little less, officially 1 million;

That is, there is a chance that over time, resistance will also appear in those strains that do not yet cause concern.

Hospital, or nosocomial, infections are increasingly common in our time. These are the infections that people contract in hospitals and other medical institutions during hospitalization and simply when visiting.

In the United States in 2011, more than 700,000 diseases caused by bacteria of the genus Klebsiella. These are mainly nosocomial infections that lead to a fairly wide range of diseases, such as pneumonia, sepsis, and wound infections. As in the case of many other bacteria, since 2001, the mass emergence of antibiotic-resistant Klebsiella began.

In one of the scientific works, scientists set out to find out how antibiotic resistance genes are common among strains of the genus Klebsiella. They found that 15 rather distant strains expressed metallo-beta-lactamase 1 (NDM-1), which is capable of destroying almost all beta-lactam antibiotics. These facts gain more strength if it is clarified that the data for these bacteria (1777 genomes) were obtained between 2011 and 2015 from patients who were in different hospitals with different infections caused by Klebsiella.

The development of antibiotic resistance can occur if:

• the patient takes antibiotics without a doctor's prescription;
• the patient does not follow the course of medication prescribed by the doctor;
• the doctor does not have the necessary qualifications;
• the patient neglects additional preventive measures (washing hands, food);
• the patient often visits medical facilities where the likelihood of becoming infected with pathogenic microorganisms is increased;
• the patient undergoes planned and unscheduled procedures or operations, after which it is often necessary to take antibiotics to avoid the development of infections;
• the patient consumes meat products from regions that do not comply with the standards for the residual content of antibiotics (for example, from Russia or China);
• the patient has reduced immunity due to diseases (HIV, chemotherapy for cancer);
• the patient is undergoing a long course of antibiotic treatment, for example, for tuberculosis.

You can read about how patients reduce the dose of an antibiotic on their own in the article “Adherence to taking medications and ways to increase it in bacterial infections”. Recently, British scientists expressed a rather controversial opinion that it is not necessary to undergo the entire course of antibiotic treatment. American doctors, however, reacted to this opinion with great skepticism.

Present (impact on the economy) and future

The problem of bacterial resistance to antibiotics covers several areas of human life at once. First of all, it is, of course, the economy. According to various estimates, the amount that the state spends on the treatment of one patient with an antibiotic-resistant infection ranges from $18,500 to $29,000. This figure is calculated for the United States, but perhaps it can also be used as an average benchmark for other countries in order to understand the scale of the phenomenon. Such an amount is spent on one patient, but if we calculate for all, it turns out that in total, $ 20,000,000,000 must be added to the total bill that the state spends on healthcare per year. And this is in addition to $ 35,000,000,000 of social expenses. In 2006, 50,000 people died due to the two most common hospital infections that led to sepsis and pneumonia. It cost the US healthcare system more than $8,000,000,000.

We have previously written about the current situation with antibiotic resistance and strategies to prevent it: “ Confrontation with resistant bacteria: our defeats, victories and plans for the future » .

If the first and second line antibiotics do not work, then either increase the doses in the hope that they will work, or use the next line of antibiotics. In both cases, there is a high probability of increased toxicity of the drug and side effects. In addition, a larger dose or a new drug will likely cost more than the previous treatment. This affects the amount spent on treatment by the state and the patient himself. And also for the duration of the patient's stay in the hospital or on sick leave, the number of visits to the doctor and economic losses from the fact that the employee does not work. More days on sick leave are not empty words. Indeed, a patient with a disease caused by a resistant microorganism has an average of 12.7 days to be treated, compared to 6.4 for a normal disease.

In addition to the reasons that directly affect the economy - spending on medicines, sick pay and time spent in the hospital - there are also a little veiled. These are the reasons that affect the quality of life of people who have antibiotic-resistant infections. Some patients - schoolchildren or students - cannot fully attend classes, and therefore they may lag behind in the educational process and psychological demoralization. Patients who take courses of strong antibiotics may develop chronic diseases due to side effects. In addition to the patients themselves, the disease morally depresses their relatives and environment, and some infections are so dangerous that they have to be kept in a separate ward, where they often cannot communicate with their loved ones. Also, the existence of hospital infections and the risk of contracting them do not allow you to relax during the course of treatment. According to statistics, about 2 million Americans annually become infected with hospital infections, which eventually claim 99,000 lives. This is most often due to infection with antibiotic-resistant microorganisms. It is important to emphasize that in addition to the above and undoubtedly important economic losses, people's quality of life also suffers greatly.

Forecasts for the future vary (video 2). Some pessimistically point to $100 trillion in cumulative financial losses by 2030-2040, equating to an average annual loss of $3 trillion. For comparison, the entire annual budget of the United States is only 0.7 trillion more than this figure. The number of deaths from diseases caused by resistant microorganisms, according to WHO estimates, will approach 11-14 million by 2030-2040 and will exceed deaths from cancer.

Video 2. Lecture by Marin McKenna at TED-2015 - What do we do when antibiotics don't work any more?

The prospects for the use of antibiotics in feed for farm animals are also disappointing (video 3). In a study published in the journal PNAS, estimated that more than 63,000 tons of antibiotics were added to feed worldwide in 2010 . And this is only modest estimates. This figure is expected to increase by 67% by 2030, but, most alarmingly, it will double in Brazil, India, China, South Africa and Russia. It is clear that, since the volume of added antibiotics will increase, then the cost of funds for them will also increase. There is an opinion that the purpose of adding them to the feed is not at all to improve the health of animals, but to accelerate growth. This allows you to quickly raise animals, profit from sales and raise new ones again. But with increasing antibiotic resistance, either larger volumes of the antibiotic will have to be added, or combinations of them will have to be created. In any of these cases, the costs of farmers and the state, which often subsidizes them, for these drugs will increase. At the same time, sales of agricultural products may even decrease due to animal deaths caused by the lack of an effective antibiotic or the side effects of a new one. And also because of the fear on the part of the population, which does not want to consume products with this “enhanced” drug. Decrease in sales or increase in the price of products can make farmers more dependent on subsidies from the state, which is interested in providing the population with the essential products that the farmer provides. Also, many agricultural producers, due to the above reasons, may be on the verge of bankruptcy, and, consequently, this will lead to the fact that only large agricultural companies will remain on the market. And, as a result, there will be a monopoly of large giant companies. Such processes will negatively affect the socio-economic situation of any state.

Video 3: BBC talks about the dangers of developing antibiotic resistance in farm animals

As the science of identifying the causes of genetic diseases and their treatment is developing rapidly around the world, we are watching with interest what is happening with methods that will help humanity “get rid of harmful mutations and become healthy”, as fans of prenatal screening methods like to mention. , CRISPR-Cas9 and a method of genetic modification of embryos that is just beginning to develop. But all this may be in vain if we are unable to resist the diseases caused by resistant microorganisms. Developments are needed that will make it possible to overcome the problem of resistance, otherwise the whole world will be unhappy.

Possible changes in the ordinary life of people in the coming years:

• sale of antibiotics only by prescription (exclusively for the treatment of life-threatening diseases, and not for the prevention of banal “colds”);
• rapid tests for the degree of microorganism resistance to antibiotics;
• treatment recommendations confirmed by a second opinion or artificial intelligence;
• remote diagnosis and treatment without visiting crowded places of sick people (including places where medicines are sold);
• testing for the presence of antibiotic-resistant bacteria before surgery;
• prohibition of cosmetic procedures without proper verification;
• reducing meat consumption and increasing its price due to the rise in the cost of farming without the usual antibiotics;
• increased mortality of people at risk;
• increase in mortality from tuberculosis in countries at risk (Russia, India, China);
• limited distribution of the latest generation of antibiotics around the world to slow down the development of resistance to them;
• discrimination in access to such antibiotics based on financial status and location.

Conclusion

Less than a century has passed since the widespread use of antibiotics. At the same time, it took us less than a century for the result of this to reach grandiose proportions. The threat of antibiotic resistance has reached a global level, and it would be foolish to deny that it was we who, by our own efforts, created such an enemy for ourselves. Today, each of us feels the consequences of resistance that has already arisen and resistance that is in the process of developing when we receive prescribed antibiotics from a doctor that do not belong to the first line, but to the second or even the last. Now there are options for solving this problem, but the problems themselves are no less. Our efforts to combat rapidly developing resistant bacteria are like a race. What will happen next - time will tell.

Nikolai Durmanov, the ex-head of RUSADA, talks about this problem in a lecture “The Crisis of Medicine and Biological Threats”.

And time really puts everything in its place. Tools are beginning to appear to improve the performance of existing antibiotics, scientific groups of scientists (so far scientists, but suddenly this trend will return to pharmaceutical companies again) are working tirelessly to create and test new antibiotics. You can read about all this and perk up in the second article of the cycle.

Superbug Solutions is a sponsor of a special project on antibiotic resistance

Company Superbug Solutions UK Ltd. ("Superbug Solutions", UK) is one of the leading companies engaged in unique research and development solutions in the field of creation of highly effective binary antimicrobials of the new generation. In June 2017, Superbug Solutions received a certificate from Horizon 2020, the largest research and innovation program in the history of the European Union, certifying that the company's technologies and developments are breakthrough in the history of research to expand the use of antibiotics.

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Modern views on the problem of antibiotic resistance and its overcoming in clinical pediatrics

We know that antibiotic resistance has always existed. Until now, there has not been (and probably hardly ever will be) an antibiotic effective against all pathogenic bacteria.

Resistance of microorganisms to antibiotics can be true and acquired. True (natural) resistance is characterized by the absence of an antibiotic target in microorganisms or the inaccessibility of the target due to initially low permeability or enzymatic inactivation. When bacteria are naturally resistant, antibiotics are clinically ineffective.

Acquired resistance is understood as the property of individual strains of bacteria to remain viable at those concentrations of antibiotics that suppress the bulk of the microbial population. The emergence of acquired resistance in bacteria is not necessarily accompanied by a decrease in the clinical effectiveness of the antibiotic. The formation of resistance in all cases is genetically determined - the acquisition of new genetic information or a change in the level of expression of one's own genes.

The following biochemical mechanisms of bacterial resistance to antibiotics are known: modification of the target of action, inactivation of the antibiotic, active removal of the antibiotic from the microbial cell (efflux), violation of the permeability of the external structures of the microbial cell, and the formation of a metabolic shunt.

The reasons for the development of resistance of microorganisms to antibiotics are diverse, among them a significant place is occupied by the irrationality, and sometimes the fallacy of the use of drugs.

1. Unreasonable prescription of antibacterial agents.

An indication for the appointment of an antibacterial drug is a documented or suspected bacterial infection. The most common mistake in outpatient practice, observed in 30-70% of cases, is the prescription of antibacterial drugs for viral infections.

2. Mistakes in choosing an antibacterial drug.

The antibiotic should be selected taking into account the following main criteria: the spectrum of antimicrobial activity of the drug in vitro, the regional level of resistance of pathogens to the antibiotic, proven efficacy in controlled clinical trials.

3. Errors in choosing the dosage regimen of the antibacterial drug.

Errors in choosing the optimal dose of an antibacterial agent can be both in insufficient and excessive doses of the prescribed drug, as well as in the wrong choice of intervals between injections. If the antibiotic dose is insufficient and does not create concentrations in the blood and tissues of the respiratory tract that exceed the minimum inhibitory concentrations of the main infectious agents, which is a condition for the eradication of the corresponding pathogen, then this becomes not only one of the reasons for the ineffectiveness of therapy, but also creates real prerequisites for the formation of resistance of microorganisms. .

The wrong choice of intervals between the administration of antibacterial drugs is usually due not so much to the difficulties of parenteral administration of drugs on an outpatient basis or the negative mood of patients, but to the ignorance of practitioners about some pharmacodynamic and pharmacokinetic features of drugs that should determine their dosing regimen.

4. Mistakes in the combined prescription of antibiotics.

One of the mistakes of antibiotic therapy for community-acquired respiratory infections is the unreasonable prescription of a combination of antibiotics. In the current situation, with a wide arsenal of highly effective broad-spectrum antibacterial drugs, the indications for combined antibiotic therapy are significantly narrowed, and the priority in the treatment of many infections remains with monotherapy.

5. Errors associated with the duration of antibiotic therapy.

In particular, at present, in some cases, unreasonably long antibiotic therapy is carried out in children. Such an erroneous tactic is primarily due to an insufficient understanding of the purpose of the antibiotic therapy itself, which is primarily to eradicate the pathogen or suppress its further growth, i.e. aimed at suppressing microbial aggression.

In addition to these errors in the prescription of antibacterial drugs, the development of antibiotic resistance is facilitated by the social problem of inadequate access to drugs, which leads to the appearance on the market of low-quality but cheap drugs, the rapid development of resistance to them and, as a result, the prolongation of the disease.

In general, the development of antibiotic resistance of microorganisms is associated with biochemical mechanisms developed in the course of evolution. There are the following ways of realization of antibiotic resistance in bacteria: modification of the target of antibiotic action, inactivation of the antibiotic itself, decrease in the permeability of the external structures of bacterial cells, formation of new metabolic pathways, and active removal of the antibiotic from the bacterial cell. Different bacteria have their own resistance development mechanisms.

Bacterial resistance to beta-lactam antibiotics develops when normal penicillin-binding proteins (PBPs) change; gaining the ability to produce additional PVR with low affinity for beta-lactams; excessive production of normal PBPs (PBP-4 and -5) with a lower affinity for beta-lactam antibiotics than PBP-1, -2, -3. In gram-positive microorganisms, the cytoplasmic membrane is relatively porous and directly adjacent to the peptidoglycan matrix, and therefore cephalosporins quite easily reach RVR. In contrast, the outer membrane of gram-negative microorganisms has a much more complex structure: it consists of lipids, polysaccharides and proteins, which is an obstacle to the penetration of cephalosporins into the periplasmic space of a microbial cell.

A decrease in the affinity of PVR for beta-lactam antibiotics is considered as the leading mechanism for the formation of resistance. Neisseria gonorrhea and S treptococcus pneumoniae to penicillin. Methicillin-resistant strains Staphylococcus aureus(MRSA) produce PBP-2 (PBP-2a), which are characterized by a significant decrease in affinity for penicillin-resistant penicillins and cephalosporins. The ability of these "new" PBP-2a to replace essential PBPs (with higher affinity for beta-lactams) eventually results in MRSA resistance to all cephalosporins.

Undoubtedly, objectively, the most clinically significant mechanism for the development of resistance of gram-negative bacteria to cephalosporins is beta-lactamase production.

Beta-lactamases are widely distributed among gram-negative microorganisms, and are also produced by a number of gram-positive bacteria (staphylococci). To date, more than 200 types of enzymes are known. Recently, up to 90% of resistant strains of bacteria isolated in the clinic are capable of producing beta-lactamases, which determines their resistance.

Not so long ago, the so-called extended-spectrum beta-lactamases encoded by plasmids (extended-spectrum beta-lactamases - ESBL) were also discovered. ESBLs are derived from TEM-1, TEM-2, or SHV-1 due to a point mutation in the active site of enzymes and are predominantly produced Klebsiella pneumoniae. ESBL production is associated with a high level of resistance to aztreonam and third-generation cephalosporins - ceftazidime and others.

Production of beta-lactamases is under the control of chromosomal or plasmid genes, and their production can be induced by antibiotics or mediated by constitutional factors in the growth and distribution of bacterial resistance with which plasmids carry genetic material. The genes encoding antibiotic resistance either arise as a result of mutations or get inside the microbes from the outside. For example, when resistant and susceptible bacteria are conjugated, resistance genes can be transferred using plasmids. Plasmids are small genetic elements in the form of DNA strands enclosed in a ring, capable of transferring from one to several resistance genes not only among bacteria of the same species, but also among microbes of different species.

In addition to plasmids, resistance genes can enter bacteria with the help of bacteriophages or be captured by microbes from the environment. In the latter case, free DNA of dead bacteria are carriers of resistance genes. However, the introduction of resistance genes by bacteriophages or the capture of free DNA containing such genes does not mean that their new host has become resistant to antibiotics. For the acquisition of resistance, it is necessary that the genes encoding it be incorporated into plasmids or into bacterial chromosomes.

Inactivation of beta-lactam antibiotics by beta-lactamase at the molecular level is presented as follows. Beta-lactamases contain stable combinations of amino acids. These groups of amino acids form a cavity into which the beta-lactam enters such that the serine at the center cuts the beta-lactam bond. As a result of the reaction of the free hydroxyl group of the amino acid serine, which is part of the active site of the enzyme, with the beta-lactam ring, an unstable acyl ester complex is formed, which rapidly undergoes hydrolysis. As a result of hydrolysis, the active enzyme molecule and the destroyed antibiotic molecule are released.

From a practical point of view, when characterizing beta-lactamases, it is necessary to take into account several parameters: substrate specificity (the ability to hydrolyze individual beta-lactam antibiotics), sensitivity to the action of inhibitors, and gene localization.

The generally accepted classification of Richmond and Sykes divides beta-lactamases into 5 classes depending on the effect on antibiotics (according to Yu.B. Belousov, 6 types are distinguished). Class I includes enzymes that break down cephalosporins, class II includes penicillins, and class III and IV include various broad-spectrum antibiotics. Class V includes enzymes that break down isoxazolylpenicillins. Chromosome-associated beta-lactamases (I, II, V) cleave penicillins, cephalosporins, and plasmid-associated (III and IV) cleave broad-spectrum penicillins. In table. 1 shows the classification of beta-lactamase according to K. Bush.

Individual members of the family Enterobacteriaceae(Enterobacter spp., Citrobacter freundii, Morganella morganii, Serratia marcescens, Providencia spp.), as well as Pseudomonasaeruginosa demonstrate the ability to produce inducible chromosomal cephalosporinases, characterized by a high affinity for cephamycins and third-generation cephalosporins. Induction or stable "derepression" of these chromosomal beta-lactamases during the period of "pressure" (use) of cephamycins or third-generation cephalosporins will eventually lead to the formation of resistance to all available cephalosporins. The spread of this form of resistance increases in cases of treatment of infections, primarily caused by Enterobacter cloaceae and Pseudomonas aeruginosa, broad-spectrum cephalosporins.

Chromosomal beta-lactamases produced by gram-negative bacteria are divided into 4 groups. The 1st group includes chromosomal cephalosporinases (I class of enzymes according to Richmond - Sykes), the 2nd group of enzymes cleaves cephalosporins, in particular cefuroxime (cefuroximases), the 3rd group includes beta-lactamases of a wide spectrum of activity, the 4th group - Enzymes produced by anaerobes.

Chromosomal cephalosporinases are divided into two subtypes. The first group includes beta-lactamases produced by E.coli, Shigella, P. mirabilis; in the presence of beta-lactam antibiotics, they do not increase the production of beta-lactamase. In the same time P.aeruginosae, P. rettgeri, Morganella morganii, E.cloaceae, E.aerogenes, Citrobacter, Serratia spp. can produce large amounts of enzymes in the presence of beta-lactam antibiotics (second subtype).

For infection caused P.aeruginosae, the production of beta-lactamase is not the main mechanism of resistance, i.e. only 4-5% of resistant forms are due to the production of plasmids and chromosome-associated beta-lactamases. Basically, resistance is associated with a violation of the permeability of the bacterial wall and an abnormal structure of the PSP.

Chromosomal cefuroximases are low molecular weight compounds that are active in vitro against cefuroxime and are partially inactivated by clavulanic acid. Cefuroximases are produced P. vulgaris, P. cepali, P. pseudomallei. Labile first-generation cephalosporins stimulate the production of this type of beta-lactamase. Possible induction of cefuroximases and stable cephalosporins. Klebsiella synthesize chromosomally determined class IV beta-lactamases, which destroy penicillin, ampicillin, first-generation cephalosporins (broad-spectrum beta-lactamases), and other cephalosporins.

Chromosomal beta-lactamases of Gram-negative bacteria ( Morganella, Enterobacter, Pseudomonas) are more intensively produced in the presence of ampicillin and cefoxitin. However, their production and activity are inhibited by clavulanic acid and especially sulbactam.

Plasmid-associated beta-lactamases produced by gram-negative bacteria, primarily E. coli and P.aeruginosae, determine the overwhelming number of nosocomial strains resistant to modern antibiotics. Numerous beta-lactamase enzymes inactivate not only penicillins, but also oral cephalosporins and first-generation drugs, as well as cefomandol, cefazolin, and cefoperazone. Enzymes such as PSE-2, OXA-3 hydrolyze and determine the low activity of ceftriaxone and ceftazidime. The stability of cefoxitin, cefotetan, and lactamocef to enzymes such as SHV-2 and CTX-1 has been described.

Since beta-lactamases play an important role in the ecology of a number of microorganisms, they are widely distributed in nature. So, in the chromosomes of many species of gram-negative microorganisms, beta-lactamase genes are found in natural conditions. It is obvious that the introduction of antibiotics into medical practice has radically changed the biology of microorganisms. Although the details of this process are unknown, it can be assumed that some of the chromosomal beta-lactamases were mobilized into mobile genetic elements (plasmids and transposons). The selective advantages conferred on microorganisms by the possession of these enzymes have led to the rapid spread of the latter among clinically relevant pathogens.

The most common enzymes with chromosomal localization of genes are class C beta-lactamases (group 1 according to Bush). The genes for these enzymes are found on the chromosomes of almost all Gram-negative bacteria. Class C beta-lactamases with chromosomal localization of genes are characterized by certain features of expression. Some microorganisms (for example, E.coli) chromosomal beta-lactamases are constantly expressed, but at a very low level, insufficient even for the hydrolysis of ampicillin.

For microorganisms of the group Enterobacter, Serratia, Morganella and others, an inducible type of expression is characteristic. In the absence of antibiotics in the environment, the enzyme is practically not produced, but after contact with some beta-lactams, the rate of synthesis increases sharply. In violation of regulatory mechanisms, constant overproduction of the enzyme is possible.

Despite the fact that more than 20 class C beta-lactamases localized on plasmids have already been described, these enzymes have not yet become widespread, but in the near future they may become a real clinical problem.

Chromosomal beta-lactamases K.pneumoniae, K.oxytoca, C. diversus and P. vulgaris belong to class A, they are also characterized by differences in expression. However, even in the case of hyperproduction of these enzymes, microorganisms remain sensitive to some third-generation cephalosporins. The chromosomal beta-lactamases of Klebsiella belong to the 2be group according to Bush, and the beta-lactamases C. diversus and P. vulgaris- to group 2e.

For reasons that are not entirely clear, the mobilization of class A beta-lactamases to mobile genetic elements is more efficient than that of class C enzymes. Thus, there is every reason to assume that SHV1 plasmid beta-lactamases, which are widespread among gram-negative microorganisms, and their derivatives originated from chromosomal beta-lactamases. K.pneumoniae.

Historically, the first beta-lactamases to cause serious clinical problems were staphylococcal beta-lactamases (Bush group 2a). These enzymes effectively hydrolyze natural and semi-synthetic penicillins, partial hydrolysis of first generation cephalosporins is also possible, they are sensitive to the action of inhibitors (clavulanate, sulbactam and tazobactam).

Enzyme genes are localized on plasmids, which ensures their rapid intra- and interspecies distribution among Gram-positive microorganisms. Already by the mid-1950s, in a number of regions, more than 50% of staphylococcal strains produced beta-lactamase, which led to a sharp decrease in the effectiveness of penicillin. By the end of the 1990s, the frequency of beta-lactamase production among staphylococci exceeded 70-80% almost everywhere.

In gram-negative bacteria, the first class A plasmid beta-lactamase (TEM-1) was described in the early 1960s, shortly after the introduction of aminopenicillins into medical practice. Due to the plasmid localization of the genes, TEM-1 and two other class A beta-lactamases (TEM-2, SHV-1) spread within a short time among members of the family Enterobacteriaceae and other gram-negative microorganisms almost everywhere.

These enzymes are called broad-spectrum beta-lactamases. Broad-spectrum beta-lactamases are group 2b according to the Bush classification. Practically important properties of broad-spectrum beta-lactamases are the following:

- III-IV generation cephalosporins and carbapenems are resistant to them;

- the ability to hydrolyze natural and semi-synthetic penicillins, cephalosporins of the first generation, partially cefoperazone and cefamandol;

The period from the late 60s to the mid-80s was marked by the intensive development of beta-lactam antibiotics; carboxy- and ureidopenicillins, as well as three generations of cephalosporins, were introduced into practice. In terms of the level and spectrum of antimicrobial activity, as well as pharmacokinetic characteristics, these drugs were significantly superior to aminopenicillins. Most cephalosporins II and III generation, in addition, were resistant to broad-spectrum beta-lactamases.

For some time after the introduction of II-III generation cephalosporins into practice, there was practically no acquired resistance to them among enterobacteria. However, already in the early 1980s, the first reports of strains with plasmid localization of resistance determinants to these antibiotics appeared. Rather quickly it was established that this resistance is associated with the production by microorganisms of enzymes genetically related to broad-spectrum beta-lactamases (TEM-1 and SHV-1), the new enzymes were called extended-spectrum beta-lactamases (ESBL).

The first extended spectrum enzyme identified was TEM-3 beta-lactamase. To date, about 100 derivatives of the TEM-1 enzyme are known. TEM-type beta-lactamases are most often found among E.coli and K.pneumoniae, however, their detection is possible among almost all representatives Enterobacteriaceae and a number of other Gram-negative microorganisms.

According to the Bush classification, TEM- and SHV-type beta-lactamases belong to the 2be group. Practically important properties of BLRS are the following:

- the ability to hydrolyze cephalosporins I-III and, to a lesser extent, IV generation;

— carbapenems are resistant to hydrolysis;

- cefamycins (cefoxitin, cefotetan and cefmetazole) are resistant to hydrolysis;

- sensitivity to the action of inhibitors;

— plasmid localization of genes.

Among the TEM- and SHV-type beta-lactamases, enzymes with a peculiar phenotype have been described. They are not sensitive to the action of inhibitors (clavulanate and sulbactam, but not tazobactam), but their hydrolytic activity against most beta-lactams is lower than that of precursor enzymes. Enzymes, called "inhibitor-resistant TEM" (IRT), are included in group 2br according to the Bush classification. In practice, microorganisms possessing these enzymes show high resistance to protected beta-lactams, but are only moderately resistant to I-II generation cephalosporins and sensitive to III-IV generation cephalosporins. However, it should be noted that some beta-lactamases combine resistance to inhibitors and an extended spectrum of hydrolytic activity.

Enzymes, the number of representatives of which has increased quite rapidly in recent years, include CTX-type beta-lactamases (cefotaximases), which represent a clearly defined group that differs from other class A enzymes. The preferred substrate of these enzymes, in contrast to TEM- and SHV -derivatives, is not ceftazidime or cefpodoxime, but cefotaxime. Cefotaximases are found in various representatives Enterobacteriaceae(mainly for E.coli and Salmonella enterica) in geographically remote regions of the world. At the same time, the distribution of clone-related strains has been described in Eastern Europe. Salmonella typhimurium producing the CTX-M4 enzyme. According to the Bush classification, CTX-type beta-lactamases belong to the 2be group. The origin of CTX-type enzymes is unclear. A significant degree of homology is found with chromosomal beta-lactamases K.oxytoca, C. diversus, P. vulgaris, S.fonticola. A high degree of homology with chromosomal beta-lactamase has recently been established. Kluyvera ascorbata.

There are also a number of rare enzymes belonging to class A and having a phenotype characteristic of ESBL (the ability to hydrolyze third-generation cephalosporins and sensitivity to inhibitors). These enzymes (BES-1, FEC-1, GES-1, CME-1, PER-1, PER-2, SFO-1, TLA-1 and VEB-1) have been isolated from a limited number of strains of various types of microorganisms in various regions. world from South America to Japan. The listed enzymes differ in their preferred substrates (certain representatives of third-generation cephalosporins). Most of these enzymes were described after the publication of Bush et al., and therefore their position in the classification has not been determined.

ESBL also includes class D enzymes. Their precursors, broad-spectrum beta-lactamases, which hydrolyze predominantly penicillin and oxacillin, are weakly sensitive to inhibitors, are distributed mainly in Turkey and France among P.aeruginosa. The genes for these enzymes are usually localized on plasmids. Most of the enzymes showing the extended spectrum phenotype (preferential hydrolysis of cefotaxime and ceftriaxone - OXA-11, -13, -14, -15, -16, -17, -8, -19, -28) are derived from beta-lactamase OXA- ten. According to the Bush classification, OXA-type beta-lactamases belong to group 2d.

Bush identifies several more groups of enzymes that differ significantly in properties (including the spectrum of action), but are usually not considered as extended-spectrum beta-lactamases. For enzymes from group 2, the predominant substrates are penicillins and carbenicillin, they are found among P.aeruginosa, Aeromonas hydrophilia, Vibrio cholerae, Acinetobacter calcoaceticus and some other gram-negative and gram-positive microorganisms, genes are more often localized on chromosomes.

For group 2e enzymes, cephalosporins are the predominant substrate, chromosomal inducible cephalosporinases are considered as a typical example. P. vulgaris. Beta-lactamases of this group are also described in Bacteroides fragilis and, less commonly, other microorganisms.

Group 2f includes rare class A enzymes capable of hydrolyzing most beta-lactams, including carbapenems. Livermore classifies these enzymes as extended-spectrum beta-lactamases, other authors do not.

In addition to the listed beta-lactamases, it is necessary to mention the last two groups of enzymes included in the Bush classification. Group 3 enzymes include rare but potentially extremely important class B metallo-beta-lactamases, regularly found among Stenotrophomonas maltophilia and rarely found in other microorganisms ( B. fragilis, A. hydrophila, P.aeruginosa and etc.). A distinctive feature of these enzymes is the ability to hydrolyze carbapenems. Group 4 includes poorly studied penicillinases P.aeruginosa suppressed by clavulanic acid.

The incidence of ESBL varies greatly in certain geographic regions. Thus, according to the multicenter study MYSTIC, in Europe, the highest incidence of ESBL is consistently noted in Russia and Poland (more than 30% among all studied strains of enterobacteria). In some medical institutions of the Russian Federation, the frequency of ESBL production among Klebsiella spp. exceeds 90%. Depending on the specifics of the medical institution, various mechanisms of resistance may be the most common in it (methicillin resistance, resistance to fluoroquinolones, hyperproduction of chromosomal beta-lactamases, etc.).

ESBLs, as already mentioned, have a wide spectrum of activity; to one degree or another, they hydrolyze almost all beta-lactam antibiotics, with the exception of cephamycins and carbapenems.

However, the presence in a microorganism of the determinants of resistance to any antibiotic does not always mean a clinical failure in the treatment with this drug. Thus, there are reports of high efficiency of III generation cephalosporins in the treatment of infections caused by strains producing ESBL.

All over the world, in order to improve the effectiveness and safety of antibacterial and antiviral agents and prevent the development of antibiotic resistance, societies and associations are being created, declarations are being adopted, and educational programs on rational antibiotic therapy are being developed. The most important of them include:

- “Public health action plan to combat antibiotic resistance”, proposed by the American Society for Microbiology and several US agencies, 2000;

— WHO Global Strategy to Contain Antibiotic Resistance, 2001.

In addition, Canada (2002) adopted the World Declaration on Combating Antimicrobial Resistance, which states that antibiotic resistance correlates with their clinical failure, it is man-made, and only man can solve this problem, and the unreasonable use of antibiotics by the population, misconceptions and underestimation of the problem of resistance by doctors and pharmacists who prescribe antibiotics can lead to the spread of resistance.

In our country, in 2002, according to the order of the Ministry of Health of Ukraine No. 489/111 dated December 24, 2002, a commission was established to control the rational use of antibacterial and antiviral agents.

The main tasks in the study of antibiotic sensitivity and antibiotic resistance are as follows:

— development of local and regional standards for the prevention and treatment of hospital and community-acquired infections;

- substantiation of measures to limit the spread of antibiotic resistance in hospitals;

— identifying the initial signs of the formation of new sustainability mechanisms;

— identification of patterns of global spread of individual resistance determinants and development of measures to limit it.

— implementation of a long-term forecast of the spread of individual resistance mechanisms and substantiation of directions for the development of new antibacterial drugs.

Antibiotic resistance and antibiotic sensitivity are studied both by "point" methods (within the same institution, district, state), and through dynamic observations of the spread of resistance.

It is difficult to compare data obtained using commercial antibiotic susceptibility testing systems from different manufacturers. Further complicating the situation are the existence of different national sensitivity criteria. Thus, only among European countries, national sensitivity criteria exist in France, Great Britain, Germany and a number of others. In individual institutions and laboratories, the methods for collecting material and assessing the clinical significance of isolates often differ significantly.

However, it should be noted that the use of an antibiotic does not always lead to antibiotic resistance (evidence of this is the sensitivity Enterococcus faecalis to ampicillin, which has not changed for decades) and, moreover, does not depend on the duration of use (resistance can develop during the first two years of its use or even at the stage of clinical trials).

There are several ways to overcome bacterial resistance to antibiotics. One of them is the protection of known antibiotics from being destroyed by bacterial enzymes or from being removed from the cell by means of membrane pumps. This is how "protected" penicillins appeared - combinations of semi-synthetic penicillins with bacterial beta-lactamase inhibitors. There are a number of compounds that inhibit the production of beta-lactamase, some of them have found their application in clinical practice:

- clavulanic acid;

- penicillanic acids;

- sulbactam (penicillanic acid sulfone);

- 6-chloropenicillanic acid;

- 6-iodopenicillanic acid;

- 6-bromopenicillanic acid;

- 6-acetylpenicillanic acid.

There are two types of beta-lactamase inhibitors. The first group includes antibiotics that are resistant to enzymes. Such antibiotics, in addition to antibacterial activity, have beta-lactamase inhibitory properties, which are manifested at high concentrations of antibiotics. These include methicillin and isoxazolylpenicillins, monocyclic beta-lactams such as carbapenem (thienamycin).

The second group consists of beta-lactamase inhibitors, which exhibit inhibitory activity at low concentrations and antibacterial properties at high concentrations. Examples include clavulanic acid, halogenated penicillanic acids, penicillanic acid sulfone (sulbactam). Clavulanic acid and sulbactam block the hydrolysis of penicillin by staphylococci.

The most widely used beta-lactamase inhibitors are clavulanic acid and sulbactam, which have hydrolytic activity. Sulbactam blocks beta-lactamase II, III, IV and V classes, as well as chromosome-mediated class I cephalosporinases. Clavulanic acid has similar properties. The difference between the drugs is that at much lower concentrations, sulbactam blocks the formation of chromosome-mediated beta-lactamases, and clavulanic acid blocks the formation of plasmid-associated enzymes. Moreover, sulbactam has an irreversible inhibitory effect on a number of lactamases. Inclusion of the beta-lactamase inhibitor clavulanic acid in the medium increases the sensitivity of penicillin-resistant staphylococci from 4 to 0.12 μg/ml.

Combinations of antibiotics also appear to be promising approaches to overcome bacterial resistance to antibiotics; conducting targeted and narrowly targeted antibiotic therapy; synthesis of new compounds belonging to known classes of antibiotics; search for fundamentally new classes of antibacterial drugs.

In order to prevent the development of resistance of microorganisms to drugs, the following principles should be followed:

1. Carry out therapy with the use of antibacterial drugs in maximum doses until the disease is completely overcome (especially in severe cases); the preferred route of drug administration is parenteral (taking into account the localization of the process).

2. Periodically replace widely used drugs with newly created or rarely prescribed (reserve) ones.

3. Theoretically, the combined use of a number of drugs is justified.

4. Drugs to which microorganisms develop resistance of the streptomycin type should not be prescribed as monotherapy.

5. Do not replace one antibacterial drug with another, to which there is cross-resistance.

6. To antibacterial drugs prescribed prophylactically or externally (especially in aerosol form), resistance develops faster than when they are administered parenterally or orally. Topical use of antibiotics should be kept to a minimum. In this case, as a rule, agents are used that are not used for systemic treatment and with a low risk of rapid development of resistance to them.

7. Evaluate the type of antibacterial drug (about once a year), which is most often used for therapeutic purposes, and analyze the results of treatment. It is necessary to distinguish between antibacterial drugs used most often and in severe cases, reserve and deep reserve.

8. Systematize diseases depending on the location of the focus of inflammation and the severity of the patient's condition; select antibacterial drugs for use in the relevant area (organ or tissue) and for use in exceptionally severe cases, and their use must be authorized by competent persons who are specifically involved in antibacterial therapy.

9. Periodically assess the type of pathogen and the resistance of strains of microorganisms circulating in the hospital environment, outline control measures to prevent nosocomial infection.

10. With the uncontrolled use of antibacterial agents, the virulence of infectious agents increases and drug-resistant forms appear.

11. Limit the use in the food industry and veterinary medicine of those drugs that are used to treat people.

12. As a way to reduce the resistance of microorganisms, the use of drugs with a narrow spectrum of action is recommended.

DECLARATION

on Combating Antimicrobial Resistance, adopted on World Resistance Day (September 16, 2000, Toronto, Ontario, Canada)

We have found the enemy, and the enemy is us.

Recognized:

1. Antimicrobials (APs) are non-renewable resources.

2. Resistance correlates with clinical failure.

3. Resistance is created by man, and only man can solve this problem.

4. Antibiotics are social drugs.

5. Excessive use of AP by the population, misconceptions and underestimation of the problem of resistance by doctors and pharmacists who prescribe AP, lead to the spread of resistance.

6. The use of AP in agriculture and veterinary medicine contributes to the accumulation of resistance in the environment.

Actions:

1. Resistance monitoring and epidemiological surveillance should become routine both in the clinic and in the hospital.

2. Worldwide, the use of antibiotics as growth promoters in livestock must be stopped.

3. Rational use of AP is the main measure to reduce resistance.

4. Creation of educational programs for doctors and pharmacists who prescribe AP.

5. Development of new AP.

Offers:

1. It is necessary to create specialized institutions for the introduction of new AP and control over the development of resistance.

2. Committees for the control of AP should be established both in all medical institutions in which AP is prescribed, and in countries and regions to develop and implement policies for their use.

3. The duration of treatment and dosing regimens of AP should be reviewed in accordance with the structure of resistance.

4. It is advisable to conduct studies to determine the most active drug in the groups of antibiotics to control the development of resistance.

5. It is necessary to reconsider approaches to the use of AP for preventive and therapeutic purposes in veterinary medicine.

7. Development of antibiotics that specifically act on pathogens or are tropic to various organs and systems of the human body.

9. Pay more attention to educational work among the population.

WHO global strategy to contain antimicrobial resistance

On September 11, 2001, the World Health Organization released the Global Strategy to Contain Antimicrobial Resistance. This program aims to ensure the effectiveness of life-saving medicines such as antibiotics, not only for the current generation of people, but also in the future. Without concerted action by all countries, many of the great discoveries made by medical scientists over the past 50 years may lose their significance due to the spread of antibiotic resistance.

Antibiotics are one of the most significant discoveries of the 20th century. Thanks to them, it became possible to treat and cure those diseases that were previously fatal (tuberculosis, meningitis, scarlet fever, pneumonia). If mankind fails to protect this greatest achievement of medical science, it will enter the post-antibiotic era.

Over the past 5 years, more than $17 million has been spent by the pharmaceutical industry on research and development of drugs used to treat infectious diseases. If drug resistance develops rapidly in microorganisms, most of these investments may be lost.

The WHO strategy to contain antimicrobial resistance concerns everyone involved in one way or another in the use or prescription of antibiotics, from patients to physicians, from hospital administrators to ministers of health. This strategy is the result of 3 years of work by experts from WHO and collaborating organizations. It aims to promote the prudent use of antibiotics to minimize resistance and enable future generations to use effective antimicrobials.

Informed patients will be able not to put pressure on doctors to prescribe antibiotics. Educated physicians will prescribe only those drugs that are actually required to treat the patient. Hospital administrators will be able to conduct detailed monitoring of the effectiveness of medicines in the field. Ministers of health will be able to ensure that most drugs that are really needed are available for use, while ineffective drugs are not used.

The use of antibiotics in the food industry also contributes to the growth of antibiotic resistance. To date, 50% of all antibiotics produced are used in agriculture not only to treat sick animals, but also as growth stimulants for cattle and birds. Resistant microorganisms can be transmitted from animals to humans. To prevent this, WHO recommends a series of actions, including mandatory prescription of all antibiotics used in animals and phase-out of antibiotics used as growth promoters.

Antibiotic resistance is a natural biological process. We now live in a world where antibiotic resistance is spreading rapidly and a growing number of life-saving drugs are becoming ineffective. Microbial resistance has now been documented against antibiotics used to treat meningitis, sexually transmitted diseases, hospital infections, and even a new class of antiretroviral drugs used to treat HIV infection. In many countries, Mycobacterium tuberculosis is resistant to at least two of the most effective drugs used to treat tuberculosis.

This problem applies equally to both highly developed and industrialized and developing countries. The overuse of antibiotics in many developed countries, the short duration of treatment in the poor - ultimately creates the same threat to humanity as a whole.

Antibiotic resistance is a global problem. There is no country that can afford to ignore it, and no country that can afford not to respond to it. Only simultaneous action to curb the growth of antibiotic resistance in each individual country will be able to produce positive results throughout the world.

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In recent years, the importance of studying microorganisms that can cause pathological changes in the human body has been growing significantly. The relevance of the topic is determined by the increasing attention to the problem of microorganism resistance to antibiotics, which is becoming one of the factors leading to the containment of the widespread use of antibiotics in medical practice. This article is devoted to the study of the overall picture of the isolated pathogens and antibiotic resistance of the most common. In the course of the work, the data of bacteriological studies of biological material from patients of the clinical hospital and antibiograms for 2013-2015 were studied. According to the general information obtained, the number of isolated microorganisms and antibiograms is steadily growing. According to the results obtained in the course of studying the resistance of isolated microorganisms to antibiotics of various groups, it is worth noting its variability first of all. To prescribe adequate therapy and prevent adverse outcomes, it is necessary to obtain timely data on the spectrum and level of antibiotic resistance of the pathogen in each case.

Microorganisms

antibiotic resistance

treatment of infections

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4. Sidorenko S.V. Research on the spread of antibiotic resistance: practical implications for medicine//Infections and Antimicrobial Therapy.-2002, 4(2): P.38-41.

5. Sidorenko S.V. Clinical significance of antibiotic resistance of gram-positive microorganisms // Infections and antimicrobial therapy. 2003, 5(2): pp.3–15.

In recent years, the importance of studying microorganisms that can cause pathological changes in the human body has been growing significantly. New species, their properties, influence on the integrity of the organism, biochemical processes occurring in it are being discovered and studied. And along with this, there is increasing attention to the problem of microorganism resistance to antibiotics, which is becoming one of the factors leading to the containment of the widespread use of antibiotics in medical practice. Various approaches to the practical use of these drugs are being developed to reduce the occurrence of resistant forms.

The aim of our work was to study the overall picture of the isolated pathogens and antibiotic resistance of the most common.

In the course of the work, the data of bacteriological studies of biological material from patients of the clinical hospital and antibiograms for 2013-2015 were studied.

According to the general information obtained, the number of isolated microorganisms and antibiograms is steadily increasing (Table 1).

Table 1. General information.

Basically, the following pathogens were isolated: about a third - Enterobacteria, a third - Staphylococcus, the rest (Streptococci, non-fermenting bacteria, Candida fungi) are slightly less. At the same time, gram-positive coccal flora was more often isolated from the upper respiratory tract, ENT organs, wounds; gram-negative rods - more often from sputum, wounds, urine.

The pattern of antibiotic resistance of S. aureus over the years under study does not allow us to identify unambiguous patterns, which is quite expected. So, for example, resistance to penicillin tends to decrease (however, it is at a fairly high level), and to macrolides it increases (table 2).

Table 2. Resistance of S. aureus.

In accordance with the result obtained in the treatment of this pathogen, effective drugs (resistance to which is falling) are: Cephalosporins of I-II generations, "Protected" Penicillins, Vancomycin, Linezolid, Aminoglycosides, Fluoroquinolones, Furan; undesirable - Penicillins, Macrolides.

As for the studied streptococci, group A pyogenic streptococcus retains high sensitivity to traditional antibiotics, that is, their treatment is quite effective. Variations occur among isolated group B or C streptococci, where resistance gradually increases (Table 3). For treatment, Penicillins, Cephalosporins, Fluoroquinolones should be used, and Macrolides, Aminoglycosides, Sulfonamides should not be used.

Table 3. Streptococcus resistance.

Enterococci are more resistant by nature, so the range of choice of drugs is very narrow initially: "Protected" Penicillins, Vancomycin, Linezolid, Furan. The growth of resistance, according to the results of the study, is not observed. "Simple" Penicillins, Fluoroquinolones remain undesirable for use. It is important to consider that Enterococci have species resistance to Macrolides, Cephalosporins, Aminoglycosides.

A third of the isolated clinically significant microorganisms are Enterobacteria. Isolated from patients of the departments of Hematology, Urology, Nephrology, they are often low-resistant, in contrast to those sown in patients of intensive care units (Table 4), which is also confirmed in all-Russian studies. When prescribing antimicrobial drugs, a choice should be made in favor of the following effective groups: "Protected" Amino- and Ureido-Penicillins, "Protected" Cephalosporins, Carbapenems, Furan. It is undesirable to use Penicillins, Cephalosporins, Fluoroquinolones, Aminoglycosides, resistance to which has increased in the last year.

Table 4. Resistance of Enterobacteria.

According to the results obtained in the course of studying the resistance of isolated microorganisms to antibiotics of various groups, it is worth noting its variability first of all. Accordingly, a very important point is the periodic monitoring of the dynamics and the application of the data obtained in medical practice. To prescribe adequate therapy and prevent adverse outcomes, it is necessary to obtain timely data on the spectrum and level of antibiotic resistance of the pathogen in each specific case. The irrational prescription and use of antibiotics can lead to the emergence of new, more resistant strains.

Bibliographic link

In recent years, nosocomial infections are increasingly caused by gram-negative microorganisms. Microorganisms belonging to the Enterobacteriaceae and Pseudomonas families have acquired the greatest clinical significance. From the family of enterobacteria, microorganisms of the genera Escherichia, Klebsiella, Proteus, Citrobacter, Enterobacter, Serratia - have often been mentioned in the literature as causative agents of postoperative complications, sepsis, meningitis. Most enterobacteria are opportunistic microorganisms, since normally these bacteria (with the exception of the genus Serratia) are obligate or transient representatives of the intestinal microflora, causing infectious processes under certain conditions in debilitated patients.

Intestinal gram-negative bacilli with resistance to third-generation cephalosporins were first identified in the mid-1980s in Western Europe. Most of these strains (Klebsiella pneumoniae, other Klebsiella species and Escherichia coli) were resistant to all beta-lactam antibiotics, with the exception of cephamycins and carbapenems. The genes that encode information about extended spectrum beta-lactamases are localized in plasmids, which facilitates the possibility of dissemination of extended spectrum beta-lactamases among gram-negative bacteria.

Studies of epidemics of nosocomial infections caused by extended-spectrum beta-lactamase-producing enterobacteria indicated that these strains arose in response to heavy use of third-generation cephalosporins.

The prevalence of extended-spectrum beta-lactamases in gram-negative bacilli varies between countries and among institutions within the same country, with frequent dependence on the range of antibiotics used. In a large US study, 1.3 to 8.6% of clinical E. coli and K. pneumoniae strains were resistant to ceftazidime. Some of the isolates in this study have been studied more closely, and it was found that in almost 50% of the strains, resistance was due to the production of extended spectrum beta-lactamase. Over 20 extended-spectrum beta-lactamases have been identified so far.

Clinical trials of antimicrobial therapy for infections caused by extended-spectrum beta-lactamase-producing bacteria are virtually non-existent, and the control database for these pathogens consists of only anecdotal case reports and limited retrospective information from epidemiological studies. Data on the treatment of nosocomial epidemics caused by gram-negative bacteria that produce these enzymes indicate that some infections (eg, urinary tract infections) can be treated with fourth-generation cephalosporins and carbapenems, but severe infections are not always amenable to such treatment.

There is a sharp increase in the role of Enterobacter as a pathogen. Enterobacter spp. notorious due to the ability to acquire resistance to beta-lactam antibiotics during therapy, and it is due to inactivating enzymes (beta-lactamases). The emergence of multidrug-resistant strains occurs through two mechanisms. In the first case, the microorganism is exposed to an enzyme inducer (such as a beta-lactam antibiotic) and increased levels of resistance occur as long as the inducer (antibiotic) is present. In the second case, a spontaneous mutation develops in the microbial cell to a stably derepressed state. Clinically, almost all manifestations of treatment failures are explained by this. Induced beta-lactamases cause the development of multi-resistance during antibiotic therapy, including the second (cefamandol, cefoxitin) and third (ceftriaxone, ceftazidime) generations of cephalosporins, as well as antipseudomonas penicillins (ticarcillin and piperacillin).

A report of an outbreak of nosocomial infections in the neonatal intensive care unit shows how the routine use of broad-spectrum cephalosporins can lead to the emergence of resistant organisms. In this department, where for 11 years ampicillin and gentamicin were the standard empirical drugs for suspected sepsis, serious infections caused by gentamicin-resistant strains of K. pneumoniae began to appear. Gentamicin was replaced by cefotaxime and the outbreak was eradicated. But the second outbreak of severe infections caused by cefotaxime-resistant E.cloacae occurred 10 weeks later.

Heusser et al. warn of the dangers of empiric use of cephalosporins in infections of the central nervous system caused by gram-negative microorganisms, which may have inducible beta-lactamases. In this regard, alternative drugs are proposed that are not sensitive to beta-lactamases (trimethoprim / sulfamethoxazole, chloramphenicol, imipenem). Combination therapy with the addition of aminoglycosides or other antibiotics may be an acceptable alternative to cephalosporin monotherapy in the treatment of diseases caused by Enterobacter.

In the mid-1980s, Klebsiella infections became a therapeutic problem in France and Germany, as strains of K.pneumoniae appeared resistant to cefotaxime, ceftriaxone and ceftazidime, which were considered absolutely stable to the hydrolytic action of beta-lactamases. New varieties of beta-lactamases have been discovered in these bacteria. Highly resistant Klebsiella can cause nosocomial epidemics of wound infections and sepsis.

Pseudomonas is no exception in terms of the development of antibiotic resistance. All strains of P.aeruginosa have the cephalosporinase gene in their genetic code. To protect against antipseudomonas penicillins, plasmids carrying TEM-1-beta-lactamase can be imported into them. Also, genes for enzymes that hydrolyze antipseudomonas penicillins and cephalosporins are transmitted through plasmids. Aminoglycosidin-activating enzymes are also not uncommon. Even amikacin, the most stable of all aminoglycosides, is powerless. P. aeruginosa strains resistant to all aminoglycosides are becoming more and more, and for the doctor in the treatment of cystic fibrosis and burn patients, this often proves to be an insoluble problem. P.aeruginosa is increasingly resistant to imipenem as well.

Haemophilus influenzae - how long will cephalosporins work?

Fight against antibiotic resistance in bacteria

Synthesis of antibiotics of new chemical structures that are not affected by beta-lactamases (for example, quinolones), or chemical transformation of known natural structures;

Search for new beta-lactam antibiotics resistant to the hydrolytic action of beta-lactamases (new cephalosporins, monobactams, carbapenems, thienamycin);

Synthesis of beta-lactamase inhibitors.

The use of beta-lactamase inhibitors preserves the benefits of known antibiotics. Although the idea that beta-lactam structures could inhibit beta-lactamase originated as early as 1956, the clinical use of inhibitors did not begin until 1976 after the discovery clavulanic acid. Clavulanic acid acts as a "suicidal" enzyme inhibitor, causing irreversible suppression of beta-lactamases. This inhibition of beta-lactamase occurs by an acylation reaction, similar to the reaction in which a beta-lactam antibiotic binds to penicillin-binding proteins. Structurally, clavulanic acid is a beta-lactam compound. Lacking antimicrobial properties, it irreversibly binds beta-lactamases and disables them.

After the isolation of clavulanic acid, other beta-lactamase inhibitors (sulbactam and tazobactam) were subsequently obtained. In combination with beta-lactam antibiotics (ampicillin, amoxicillin, piperacillin, etc.), they exhibit a wide spectrum of activity against beta-lactamase-producing microorganisms.

Another way to combat antibiotic resistance in microorganisms is to organize monitoring of the prevalence of resistant strains through the creation of an international alert network. Identification of pathogens and determination of their properties, including sensitivity or resistance to antibiotics, must be carried out in all cases, especially when registering a nosocomial infection. The results of such studies must be summarized for each maternity hospital, hospital, microdistrict, city, region, etc. The obtained data on the epidemiological state should be periodically brought to the attention of the attending physicians. This will allow you to choose the right drug in the treatment of the child, to which the majority of strains are sensitive, and not to prescribe the one to which in the given area or medical institution the majority of strains are resistant.

Limiting the development of resistance of microorganisms to antibacterial drugs can be achieved by following certain rules, among which:

Conducting rationally based antibiotic therapy, including indications, targeted selection based on sensitivity and resistance level, dosage (low dosage is dangerous!), Duration (in accordance with the picture of the disease and individual condition) - all this involves advanced training of doctors;

It is reasonable to approach combination therapy, using it strictly according to indications;

The introduction of restrictions on the use of drugs ("barrier policy"), which implies an agreement between clinicians and microbiologists on the use of the drug only in the absence of the effectiveness of already used drugs (creation of a group of reserve antibiotics).

The development of resistance is an inevitable consequence of the widespread clinical use of antimicrobials. The variety of mechanisms by which bacteria acquire resistance to antibiotics is striking. All of this calls for efforts to find more effective ways to use available drugs to minimize the development of resistance and to identify the most effective treatments for infections caused by multidrug-resistant microorganisms.

ANTIBIOTICS AND CHEMOTHERAPY, 1998-N4, pp. 43-49.

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On September 19, 2017, a World Health Organization report was released on the problem of the difficult situation with antibiotics on our planet.

We will try to talk in detail about the problem, which should not be underestimated, because it is a serious threat to human life. This problem is called antibiotic resistance.

According to the World Health Organization, the situation on the planet is fundamentally the same in all countries. That is, antibiotic resistance is developing everywhere and it does not matter whether it is the United States or Russia.

When we say antibiotic resistance, we must understand that this is a kind of jargon. Antibiotic resistance is understood not only as resistance to antibiotics, but also to viral drugs, antifungal drugs and drugs against protozoa.

So where does antibiotic resistance come from?

Everything is pretty simple. People live on a planet that has been owned by microorganisms for three and a half billion years. These organisms are at war with each other, trying to survive. And of course, in the process of evolution, they have developed a huge number of ways to defend themselves against any type of attack.

The source of resistant microorganisms in our everyday life is medicine and agriculture. Medicine because, since 1942, for 3 generations of people, antibiotics have been used to treat all possible diseases. Of course, there is no way to do without antibiotics. Any operation, any treatment of infection requires the appointment of an antibacterial drug. With each intake of such a drug, part of the microorganisms dies, but the surviving part remains. This is what passes resistance to the next generation. And over time, superbacteria or super infections appear - microorganisms that are immune to almost any antibiotic. Such superbugs have already appeared in our everyday life and, unfortunately, they are harvesting a rich harvest of victims.

The second source of the problem is agriculture. Between 80 and 90% of all antibiotics are not used in medicine or for humans. Antibiotics are practically fed to cattle, otherwise there is no weight gain and the animal gets sick. It cannot be otherwise, because we collect millions of cattle in a limited space, keep them in non-natural conditions and feed them with those feeds that nature does not provide for this type of organism. Antibiotics are a kind of guarantee that Scott will not get sick and will gain weight. As a result, tens of thousands of tons of antibiotics end up in nature, and there, the selection of resistant strains begins, which are returned to us with food.

Of course, not everything is so simple, and the matter is not only in medicine and agriculture. Tourism and the global economy play a very important role here (when food, some raw materials, fertilizer are transported from one country to another). All this makes it impossible to somehow block the spread of superbugs.

In fact, we live in one big village, so some kind of supermicrobe that arose in one country becomes a big problem in other countries.

It is worth mentioning such an important reason for the development of antibiotic resistance as the use of drugs without a doctor's prescription. According to American statistics, approximately 50% of cases in taking antibiotics are related to viral infections. That is, any cold and a person begins to use an antibacterial drug. Not only is it ineffective (antibiotics do not work on viruses!!!), but it also leads to the emergence of more resistant types of infections.

And finally, the problem, which for many will seem surprising. We don't have any new antibiotics left. Pharmaceutical companies are simply not interested in developing new antibacterial drugs. Development usually takes up to 10 years of hard work, a lot of investment, and in the end, even if this drug gets on the market, it does not give any guarantee that resistance will not appear in a year or two.

In fact, in our medical arsenal, there are antibiotics developed many years ago. Fundamentally new antibiotics have not appeared in our medical practice for 30 years. What we have are modified and reworked old versions.

And now we have a rather serious situation. We presumptuously undertook to compete with a gigantic number of microorganisms that have their own understanding of how to live, how to survive and how to react to the most unexpected circumstances. Moreover, our antibiotics, even the most chemical ones, are not very big news for the microworld. This is because, in their mass, antibiotics, this is the experience of the microcosm itself. We peep how microbes fight each other and, drawing conclusions, create an antibacterial drug (for example, penicillin). But even the inventor of the antibiotic himself, Sir Alexander Fleming, warned that the active use of antibiotics would certainly cause the emergence of strains of microorganisms resistant to them.

In connection with the foregoing, we can derive simple rules for personal safety when using antibacterial drugs:

1. Do not rush to use an antibiotic if you or someone close to you is coughing.
2. Only use the antibiotics your doctor has prescribed for you.
3. Buy medicines only in pharmacies.
4. If you started taking the drug, be sure to complete the entire course of treatment.
5. Do not stock up on antibiotics, each medicine has its own expiration date.
6. Do not share antibiotics with other people. Each person is individually selected one or another drug.