Most of the antibiotics available on the market today come from the 80s, the so-called the golden age of antibiotic therapy. We are currently experiencing a huge disproportion between the demand for new drugs and their supply. Meanwhile, according to WHO, the post-antibiotic era has just begun. We talk to prof. dr hab. med. Waleria Hryniewicz.
- Every year, infections with bacteria resistant to antibiotics cause approx. 700 thousand. worldwide deaths
- “Improper and excessive use of antibiotics meant that the percentage of resistant strains gradually increased, taking on an avalanche character since the end of the last century” – says Prof. Waleria Hryniewicz
- Swedish scientists of bacteria of great importance in human infections, such as Pseudomonas aeruginosa and Salmonella enterica, have recently discovered the so-called the gar gene, which determines resistance to one of the newest antibiotics – plasomycin
- According to prof. Hryniewicz in Poland is the most serious problem in the field of infection medicine NewDelhi-type carbapenemase (NDM) as well as KPC and OXA-48
Monika Zieleniewska, Medonet: It looks like we are racing against bacteria. On the one hand, we are introducing a new generation of antibiotics with an ever wider spectrum of action, and on the other hand, more and more microorganisms are becoming resistant to them …
Prof. Waleria Hryniewicz: Unfortunately, this race is won by bacteria, which could mean the beginning of a post-antibiotic era for medicine. The term was first used in the “Report on Antibiotic Resistance” published by the WHO in 2014. The document emphasizes that now, even mild infections can be fatal and it is not an apocalyptic fantasy, but a real picture.
In the European Union alone, there were 2015 jobs in 33. deaths due to infections with multi-resistant microorganisms for which no effective therapy was available. In Poland, the number of such cases has been estimated at around 2200. However, the American Center for Infection Prevention and Control (CDC) in Atlanta recently reported that in the USA due to similar infections every 15 minutes. the patient dies. According to the estimates of the authors of the report prepared by the team of the eminent British economist J. O’Neill, every year in the world antibiotic-resistant infections cause approx. 700 thousand. deaths.
- Read also: The antibiotics stop working. There will be no drugs for superbugs soon?
How do scientists explain the crisis of antibiotics?
The wealth of this group of drugs lowered our vigilance. In most cases, resistant strains were isolated with the introduction of a new antibiotic, but this phenomenon was initially marginal. But it meant that the microbes knew how to defend themselves. Due to the improper and excessive use of antibiotics, the percentage of resistant strains gradually increased, taking on an avalanche-like character since the end of the last century.. Meanwhile, new antibiotics were introduced sporadically, so there was a huge disproportion between the demand, i.e. the demand for new drugs, and their supply. If appropriate action is not taken immediately, global deaths from antibiotic resistance could rise to as much as 2050 million per year by 10.
Why is the overuse of antibiotics harmful?
We must deal with this issue in at least three aspects. The first is directly related to the action of an antibiotic on humans. Remember that any drug can cause side effects. They can be mild, e.g. nausea, feel worse, but they can also cause life-threatening reactions, such as anaphylactic shock, acute liver damage or heart problems.
Moreover, the antibiotic disturbs our natural bacterial flora, which, by guarding the biological balance, prevents the excessive multiplication of harmful microorganisms (eg Clostridioides difficile, fungi), including those resistant to antibiotics.
The third negative effect of taking antibiotics is the generation of resistance among our so-called normal, friendly flora that can pass it on to bacteria capable of causing severe infections. We know that pneumococcal resistance to penicillin – an important causative agent of human infections – came from oral streptococcus, which is common to all of us without harming us. On the other hand, infection with resistant pneumococcal disease poses a serious therapeutic and epidemiological problem. There are many examples of interspecific transfer of resistance genes, and the more antibiotics we use, the more efficient this process is.
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How do bacteria develop resistance to commonly used antibiotics, and how much of a threat does this pose to us?
The mechanisms of antibiotic resistance in nature have existed for centuries, even before their discovery for medicine. Microorganisms that produce antibiotics must defend themselves against their effects and, in order not to die from their own product, they have resistance genes. Moreover, they are able to use existing physiological mechanisms to fight antibiotics: to create new structures that enable survival, and also to initiate alternative biochemical pathways if the drug is naturally blocked.
They activate various defense strategies, e.g. pump out the antibiotic, stop it from entering the cell, or deactivate it with various modifying or hydrolysing enzymes. An excellent example are the very widespread beta-lactamases hydrolyzing the most important groups of antibiotics, such as penicillins, cephalosporins or carbapenems.
It has been proven that the rate of emergence and spread of resistant bacteria depends on the level and pattern of antibiotic consumption. In countries with restrictive antibiotic policies, resistance is kept at a low level. This group includes, for example, the Scandinavian countries.
What does the term “superbugs” mean?
Bacteria are multi-antibiotic resistant, i.e. they are not susceptible to first-line or even second-line drugs, i.e. the most effective and safest ones, often resistant to all available drugs. The term was originally applied to methicillin and vancomycin insensitive multibiotic-resistant strains of staphylococcus aureus. Currently, it is used to describe strains of various species that exhibit multi-antibiotic resistance.
And the alarm pathogens?
The alarm pathogens are superbugs, and their numbers are constantly increasing. Detecting them in a patient should trigger an alarm and implement particularly restrictive measures that will prevent their further spread. Alert pathogens present one of the greatest medical challenges todayThis is due both to significant limitations of therapeutic possibilities and increased epidemic characteristics.
Reliable microbiological diagnostics, properly functioning infection control teams and epidemiological services play a huge role in limiting the spread of these strains. Three years ago, the WHO, based on an analysis of antibiotic resistance in the member states, divided multiresistant bacterial species into three groups depending on the urgency of introducing new effective antibiotics.
The critically important group includes intestinal sticks, such as Klebsiella pneumoniae and Escherichia coli, and Acinetobacter baumannii and Pseudomonas aeruginosa, which are increasingly resistant to last-resort drugs. There is also a mycobacterium tuberculosis resistant to rifampicin. The next two groups included, among others multiresistant staphylococci, Helicobacter pylori, gonococci, as well as Salmonella spp. and pneumococci.
The information that the bacteria responsible for infections outside the hospital are on this list. The broad antibiotic resistance among these pathogens may mean that infected patients should be referred for hospital treatment. However, even in medical institutions, the choice of effective therapy is limited. The Americans included gonococci in the first group not only because of their multi-resistance, but also because of their extremely effective path of spread. So, will we be treating gonorrhea in the hospital soon?
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Swedish scientists have discovered bacteria in India that contain an antibiotic resistance gene, the so-called gen gar. What is it and how can we use this knowledge?
The detection of a new gar gene is associated with the development of the so-called environmental metagenomics, i.e. the study of all DNA obtained from natural environments, which also allows us to identify microorganisms that we cannot grow in a laboratory. The discovery of the gar gene is very disturbing because it determines resistance to one of the newest antibiotics – plazomycin – registered last year.
High hopes were placed on it because it was highly active against bacterial strains resistant to the older drugs in this group (gentamicin and amikacin). Another bad news is that this gene is located on a mobile genetic element called an integron and can spread horizontally, and therefore very efficiently, between different bacterial species even in the presence of plasomycin.
The gar gene has been isolated from bacteria of great importance in human infections, such as Pseudomonas aeruginosa and Salmonella enterica. Research in India concerned material collected from the bottom of a river to which sewage was discharged. They showed the widespread dissemination of resistance genes in the environment through irresponsible human activities. Therefore, a number of countries are already considering disinfecting wastewater before it is released into the environment. Swedish researchers also emphasize the importance of detecting resistance genes in the environment at the initial stage of introducing any new antibiotic, and even before they are acquired by microorganisms.
- Read more: Scientists from the University of Gothenburg noticed that a previously unknown gene for antibiotic resistance has spread
It seems that – as in the case of viruses – we should be careful about breaking ecological barriers and intercontinental tourism.
Not only tourism, but also various natural disasters such as earthquakes, tsunamis and wars. When it comes to breaking the ecological barrier by bacteria, a good example is the rapid increase in the presence of Acinetobacter baumannii in our climate zone.
It has to do with the First Gulf War, from where it was brought to Europe and the US most likely by returning soldiers. He found excellent living conditions there, especially in the context of global warming. It is an environmental microorganism, and therefore endowed with many different mechanisms that enable it to survive and multiply. These are, for example, resistance to antibiotics, to salts, including heavy metals, and to survival in conditions of high humidity. Acinetobacter baumannii is one of the most serious problems of nosocomial infections in the world today.
However, I would like to pay particular attention to the epidemic, or rather a pandemic, which often escapes our attention. It is the spread of multiresistant bacterial strains as well as the horizontal spread of resistance determinants (genes). Resistance arises through mutations in chromosomal DNA, but also is acquired thanks to the horizontal transfer of resistance genes, e.g. on transposons and conjugation plasmids, and the acquisition of resistance as a result of genetic transformation. It is especially effective in environments where antibiotics are widely used and abused.
Regarding the contribution of tourism and long journeys to the spread of resistance, the most spectacular is the spread of strains of intestinal rods producing carbapenemases capable of hydrolyzing all beta-lactam antibiotics, including carbapenems, a group of drugs particularly important in the treatment of severe infections.
In Poland, the most common is carbapenemase of the NewDelhi type (NDM), as well as KPC and OXA-48. They were probably brought to us from India, USA and North Africa, respectively. These strains also have genes for resistance to a number of other antibiotics, which significantly limit the therapeutic options, classifying them as alarm pathogens. This is certainly the most serious problem in the field of infection medicine in Poland, and the number of cases of infections and carriers confirmed by the National Reference Center for Antimicrobial Susceptibility has already exceeded 10.
- Read more: In Poland, there are an avalanche of people infected with the deadly New Delhi bacterium. Most antibiotics don’t work for her
According to the medical literature, more than half of the patients are not saved in blood infections caused by the intestinal bacilli which produce carbapenemases. Although new antibiotics active against carbapenemase producing strains have been introduced, we still do not have any antibiotic effective in the treatment of NDM.
Several studies have been published showing that our digestive tract is easily colonized with local microorganisms during intercontinental journeys. If resistant bacteria are common there, we import them to where we live and they stay with us for several weeks. Additionally, when we take antibiotics that are resistant to them, there is an increased risk of their spreading.
Many of the resistance genes identified in the bacteria responsible for human infections are derived from environmental and zoonotic microorganisms. Thus, a pandemic of a plasmid carrying the colistin resistance gene (mcr-1) has recently been described, which has spread in Enterobacterales strains on five continents within one year. It was originally isolated from pigs in China, then in poultry and food products.
Recently, there has been much talk about halicin, an antibiotic invented by artificial intelligence. Are computers effectively replacing people in developing new drugs?
Searching for drugs with the expected properties using artificial intelligence seems not only interesting, but also very desirable. Maybe this would give you a chance to get the ideal drugs? Antibiotics that no microorganism can resist? With the help of the created computer models, it is possible to test millions of chemical compounds in a short time and select the most promising ones in terms of antibacterial activity.
Just such a “discovered” the new antibiotic is halicin, which owes its name to the HAL 9000 computer from the movie “2001: A Space Odyssey”. Studies of its in vitro activity against the multiresistant Acinetobacter baumannii strain are optimistic, but it does not work against Pseudomonas aeruginosa – another important hospital pathogen. We observe more and more proposals of potential drugs obtained by the above method, which allows to shorten the first phase of their development. Unfortunately, there are still animal and human studies to be performed to determine the safety and efficacy of the new drugs under real conditions of infection.
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Will we therefore entrust the task of creating new antibiotics to properly programmed computers in the future?
This is already partially happening. We have huge libraries of diverse compounds with known properties and mechanisms of action. We know what concentration, depending on the dose, they reach in the tissues. We know their chemical, physical and biological characteristics, including toxicity. In the case of antimicrobial drugs, we must strive to thoroughly understand the biological characteristics of the microorganism for which we want to develop an effective drug. We need to know the mechanism of causing lesions and virulence factors.
For example, if a toxin is responsible for your symptoms, the drug should suppress its production. In the case of multi-antibiotic-resistant bacteria, it is necessary to learn about the mechanisms of resistance, and if they result from the production of an enzyme that hydrolyzes the antibiotic, we look for its inhibitors. When a receptor alteration creates the resistance mechanism, we need to find one that will have an affinity for it.
Perhaps we should also develop technologies for the design of “tailor-made” antibiotics, tailored to the needs of specific people or to specific strains of bacteria?
It would be great, but … at the moment, in the first phase of treating an infection, we usually do not know the etiological factor (causing the disease), so we start the therapy with a drug with a broad spectrum of action. One bacterial species is usually responsible for many diseases occurring in different tissues of different systems. Let us take as an example the golden staphylococcus, which causes, among others, skin infections, pneumonia, sepsis. But pyogenic streptococcus and Escherichia coli are also responsible for the same infections.
Only after receiving the culture result from the microbiological laboratory, which will tell not only which microorganism caused the infection, but also what its drug susceptibility looks like, allows you to choose an antibiotic that is “tailored” to your needs. Also note that an infection caused by the same pathogen elsewhere in our body may require a different medicationbecause the effectiveness of the therapy depends on its concentration at the site of infection and, of course, the sensitivity of the etiological factor. We urgently need new antibiotics, both broad-spectrum, when the etiological factor is unknown (empirical therapy) and narrow, when we already have a microbiological test result (targeted therapy).
What about research on personalized probiotics that will adequately protect our microbiome?
So far, we have not been able to construct probiotics with the desired characteristics, we still know too little about our microbiome and its image in health and disease. It is extremely diverse, complicated, and the methods of classical breeding do not allow us to fully understand it. I hope that the more and more frequently undertaken metagenomic studies of the gastrointestinal tract will provide important information that will allow for targeted remedial interventions within the microbiome.
Maybe you also need to think about other treatment options for bacterial infections that eliminate antibiotics?
We must remember that the modern definition of an antibiotic differs from the original one, i.e. only the product of microbial metabolism. To make it easier, We currently consider antibiotics to be all antibacterial drugs, including synthetic ones, such as linezolid or fluoroquinolones. We are looking for the antibacterial properties of drugs used in other diseases. However, the question arises: should you give up their provision in the original indications? If not, we will likely generate resistance to them quickly.
There have been many discussions and research trials concerning a different approach to the fight against infections than before. Of course, the most effective way is to develop vaccines. However, with such a large variety of microbes, this is not possible due to the limitations of our knowledge of pathogenic mechanisms, as well as for technical and cost-effective reasons. We strive to reduce their pathogenicity, e.g. by limiting the production of toxins and enzymes important in the pathogenesis of infection or by depriving them of the possibility of tissue colonization, which is usually the first stage of infection. We want them to coexist peacefully with us.
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Prof. dr hab. med. Waleria Hryniewicz is a specialist in the field of medical microbiology. She headed the Department of Epidemiology and Clinical Microbiology of the National Medicines Institute. She is the chairman of the National Antibiotic Protection Program, and until 2018 she was a national consultant in the field of medical microbiology.
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