Antibiotic resistance describes the properties of microorganisms such as bacteria or fungi that enable them to weaken or completely neutralize the effect of antibiotic active substances . A resistance to antibiotics in combination or as an adaptation to extreme environmental conditions usually occurs: So are streptomycetes as soil-dwelling bacteria not only resistant to many environmental toxins, but also to virtually all antimicrobial agents currently in use. Antibiotic producers such as streptomycetes are in most cases resistant to the substances they themselves produce. According to the WHO, around 700,000 people worldwide die each year as a result of antibiotic resistance; in Germany about 6,000.
Since antibiotic resistance has been found in bacteria that have lived in isolation for four million years, researchers believe that it is a central, ancient characteristic of these creatures.
Many pathogenic (disease-causing) microorganisms have a short generation time ; their biomass can double within 20 to 30 minutes under favorable conditions. In this way, beneficial mutations can arise relatively quickly. This tendency is reinforced by a number of “mobile elements”. These are DNA segments that occur in the bacterial chromosome or outside it as plasmids , integrons , transposons and can be transferred by horizontal gene transfer. "Resistance cassettes" are passed on even between phylogenetically very distant species.
Resistance to some antibiotics develops faster than to others. So form z. Resistance to macrolides , for example, is fast because they only inhibit a certain enzyme (the translocase ) (one-step resistance pattern). If the translocase has mutated, they may no longer work. That is why there is already increasing resistance to macrolides, although they were only developed in the 1990s. In contrast, penicillin attacks six different penicillin-binding proteins (PBP). It is still used today for many indications , although it has been around for decades.
Sometimes combinations of antibiotics are used to make the development of resistance less likely and to increase the effects. A combination of antibiotics is not indicated in every case. In principle, however, it makes sense to inhibit the same metabolic pathway at different points, since the probability decreases with each antibiotic that the mutations necessary for the development of resistance occur at the same time. Therefore z. B. sulfonamides combined with other folic acid antagonists.
A 2013 study found that the intestinal flora is resistant to a large part of antibiotics even in young children . This can be related to both the early use of antibiotics (within the first year of life) and the use of antibiotics in the food industry and the initial colonization of resistant germs in the intestine, which is still aseptic at birth . The multi-resistant intestinal flora in itself is more of an advantage, as the intestinal flora is not so damaged by the administration of antibiotics. However, the resistance can also be transmitted to pathogenic germs.
An important reason for the development of resistance is the uncritical prescription of antibiotics. An example is the prescription practice for bronchitis , although only about five percent of cough disorders are caused by bacteria, the rest is caused by viruses. Since antibiotics are not effective against viruses and other germs, they are usually of little help here. On the contrary, through repeated and widespread use, resistant microorganisms are grown . If there is a real need, the antibiotics no longer work. Antibiotics should therefore only be used if they are clearly indicated. This applies, for example, to bacterial pneumonia or febrile urinary tract infection.
There is a widespread opinion that the therapy must be carried out consistently if there is a response in order to minimize the development of resistance. In the meantime, however, there are studies that state that this can even promote resistance, as other bacteria in the body are exposed to the antibiotics for longer. Accordingly, antibiotics should only be used for exactly as long as necessary, although shorter times than previously usual may be sufficient. The risk that surviving pathogenic bacteria will develop resistance is low.
Another critical point is the insufficient breakdown of antibiotics in the body. As a result, antibiotic residues get into the wastewater and bacteria develop resistance in the sewers and sewage treatment plants as a result of the selection pressure .
Bacteria can also develop resistance through underdosed antibiotics and transfer resistance genes to other bacteria. This gene exchange takes place z. B. in hospitals where different bacterial strains can come into contact with each other and are carried from bed to bed. This promotes the formation of resistance and the spread of resistant germs ( infectious hospitalism ).
Studies indicate that combination therapy with several antibiotics simultaneously promotes the development of resistance. The acceleration of the development of resistance probably depends on the combination of the respective antibiotics.
Use in animal fattening
Another important cause of the spread of resistance is the use of antibiotics for prophylactic purposes and as growth promoters in agricultural animal fattening . According to Lester A. Mitscher from the University of Kansas, almost half of the antibiotics produced worldwide are used for this purpose. Several European countries have therefore banned this practice in factory farming for food production since the mid-1990s. As a result, the resistance rate could be reduced, but the spread of resistance remains worrying. It has also been shown that the agricultural application of liquid manure leads to an increase in antibiotic-resistant bacteria in the soil. There are also indications that the corresponding resistance genes are exchanged more frequently. Because the resistance remains in the soil for a long time, it is possible for bacteria to enter the human food chain.
Since 2006, a waiting period has been stipulated across the EU between the administration of veterinary antibiotics and slaughter, during which the medication can be broken down in the animal's body (see below: Countermeasures section ). A direct transmission of resistant pathogens to humans is possible.
In 2012, almost 1,620 tons of antibiotics were used in animal fattening in Germany .
Cases of illness are now known in which certain antibiotic-resistant germs ( MRSA germs) have been transmitted from humans to animals and back to humans. The germs acquire additional resistance in the animal. They find their way, u. a. back into the human organism via the exhaust air from the stables via the respiratory tract, as well as via eaten vegetables that have been fertilized with manure . By reducing the administration of antibiotics with unchanged housing conditions, reserve antibiotics were used.
As a rule, automated and in any case standardized procedures are used. After the resistance has been determined, the germs detected are designated as S - sensitive, I - intermediate or R - resistant . The determination of resistance is used by the microbiologist and the treating physician to select a specific antibiotic therapy.
There are basically three ways of determining resistance:
Smears are on nutrient medium or in cell culture in the presence and in the absence of antibiotics cultivated . This procedure is commonly called "antibiotic resistance assessment". It is the simplest and cheapest for most organisms, but this method is not optimal for some organisms because they grow too slowly and are too laborious to cultivate (e.g. mycobacteria ).
Molecular biological methods / immunological methods
With the help of antibodies that are directed against parts of the organism in question, the presence of resistant strands or pathovars can be determined directly or indirectly. The best known methods are ELISA and Western Blot .
Evidence is provided by a targeted search for resistance genes in the genome of the respective organism. This method is currently the most accurate. Techniques such as PCR are used. Disadvantages are the often too long test duration, the higher effort and the price. A resistance gene can also be present but not expressed, which means that the strain does not show any resistance, but is recognized as resistant by this method.
Types of antibiotic resistance
Depending on the origin of the resistance, these can be divided into different classes.
- Primary resistance: Resistance is defined as primary if an antibiotic has a lack of effectiveness in a certain genus or species . For example, cephalosporins do not work on enterococci and ampicillin do not work on Pseudomonas aeruginosa
Secondary or acquired resistance: This form of resistance is characterized by the loss of the effectiveness of an antibiotic in a primarily non-resistant bacterium. It can arise spontaneously through mutation or transmission.
- Resistance through mutation: Mutations in the genome occur naturally on the order of approx. 10 −7 . The mutation rate can, however, increase by leaps and bounds if specific factors deactivate the “proof reading” of the DNA polymerase . This can be a way to acquire resistance or favorable properties more quickly. They can lead to resistance to an antibiotic, which then leads to a selection advantage when exposed to the corresponding antibiotic.
- Resistance through transmission: Bacteria can transmit genetic information to one another via the processes of transformation , transduction and conjugation , which is located on plasmids , transposons and integrons . Resistance genes can also be transferred in this way.
Depending on the mode of action and the antibiotic used, various mechanisms for reducing or neutralizing the effect developed over time.
An alternative protein is produced that has the same function as the one blocked by the antibiotic. Alternative penicillin binding proteins (PBP) are an example. PBPs are necessary for the synthesis of murein and are usually inactivated by β-lactam antibiotics . Mutations create new variants that can no longer be inactivated, making the bacterium resistant. In the case of MRSA (Methicillin Resistant Staphylococcus aureus ), for example, it is PBP2a.
The bacterium produces proteins that neutralize the antibiotic. The best-known example of this are the β-lactamases . These proteins hydrolyze β-lactams on the β-lactam ring; as a result, the antibiotic can no longer bind to the target protein, the PBP, and therefore has no effect. Escherichia coli has ESBL (called e xtended s pectrum b eta l actamases ) having a plurality of β-lactam antibiotics, such as cephalosporins and penicillins can neutralize.
Target proteins or structures in the bacterium are changed by mutations. In many vancomycin-resistant strains, murein changes . Instead of a D- alanine / D-alanine compound, a D-alanine / D- lactam compound is produced. As a result, the antibiotic used no longer binds and is ineffective.
Post-translational / post-transcriptional modifications
If an antibiotic binds to a certain point in a protein and thereby inactivates it, the binding force can be greatly reduced by a modification after translation or transcription . The antibiotic is bound very poorly or not at all. A resistance mechanism to streptomycin is based on the modification of an aspartic acid residue in the ribosomal protein S12.
Changes in the cell wall mean that the antibiotic can no longer diffuse inward. The best known example of this is the acid-resistant cell wall of mycobacteria . This enables resistance to a variety of antibiotics and toxins.
Special transport proteins ( Multidrug Resistance-Related Proteins ) release antibiotics that have penetrated the cell to the outside, so that the concentration inside the cell can be kept low enough not to cause any damage. The transporters that are responsible for this can be divided into certain classes. One example is the RND transporter (Resistance-Nodulation-Cell Division), of which Escherichia coli alone has seven different ones .
The protein inactivated by the antibiotic is produced in larger quantities than needed. The antibiotic inactivates most of the protein present, but enough functional molecules are retained to allow the cell to survive. Overexpression of PBP can lead to resistance to beta-lactams .
Alternative metabolic pathways
A metabolic product that is blocked by one antibiotic can, under certain circumstances, be replaced by another. In Staphylococcus aureus , resistance to trimethoprim can be achieved through auxotrophy of trihydrofolate. Trihydrofolate is no longer required in the metabolism, so the antibiotic that inactivates this molecule can no longer work.
Biofilms are collections of microorganisms embedded in a mucus matrix. The dense colonization leads to the excretion of various substances as protection to the outside world, and the transfer of genetic material and thus resistance genes is simplified. However, the exact mechanism is not yet known.
The expression of certain factors can greatly reduce the ability of DNA polymerase to correct errors. This makes it easier to induce mutations. The development of resistance to ciprofloxacin in an Escherichia coli strain could be prevented by deactivating the mutation factor lexA.
Penetration into body cells
In the in-vitro model with Staphylococcus aureus, it was possible to show that bacteria can penetrate epithelial cells of the lungs and are put into a kind of dormant state with greatly altered gene activity . With a reduced metabolism, the production of cell-toxic substances and the rate of division are reduced. Only when the host cell dies is the bacterium, which has been protected from antibiotics and the immune system, released and activated. Treatment with antibiotics in the model killed most of the cells within four days, but living microbes could still be detected after two weeks. This could therefore be a mechanism that contributes to chronic and recurring infections.
So-called problem germs are mainly the methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas spec., Escherichia coli and Mycobacterium tuberculosis . The Centers for Disease Control and Prevention estimates that there will be two million hospital-acquired infections in the United States in 2004, with approximately 90,000 deaths.
In therapy without pathogens assurance are against penicillin and macrolide antibiotics less sensitive pneumococci and A streptococci , much against amoxicillin sensitive Haemophilus as well as to trimethoprim or cotrimoxazole , nitrofurantoin , fosfomycin and fluoroquinolones resistant Escherichia coli observed.
Patients with immune deficiencies , such as the seriously ill or people infected with HIV , are particularly susceptible . Transplants are also at risk because these patients take immunosuppressive drugs to counteract the risk of the body's immune system rejecting the transplant.
In 2005 around three million Europeans were infected with germs that are resistant to known antibiotics - 50,000 of them died from it. Lower numbers currently apply to other industrialized nations. In England and Wales, 51 patients died of infections with resistant microbes in 1992, compared with 800 in 2002. In Sweden , Norway , the Netherlands and Denmark the resistance rates are much better because the prescriptions are less generous.
The situation is also problematic in developing countries , where the death rate from infectious diseases is 55% (including AIDS). There is often a lack of money for modern antibiotics or investments in hygiene and better or even better sanitary facilities. B. antibiotic-resistant typhoid pathogens spread quickly.
WHO (World Health Organization)
According to the WHO Global Report of April 2014, measures are required worldwide, including a. an efficient network of laboratories counts, which can quickly recognize emerging resistances and collect and pass on information obtained for rapid countermeasures. Not all countries have been able to do this so far. The WHO also recommends relatively simple measures. For example, doctors should only prescribe antibiotics if their safe use is considered really necessary. As far as possible, patients should not receive broad-spectrum antibiotics, which can have a simultaneous effect against various pathogens, since these drugs no longer respond to many pathogens. The WHO experts advise using targeted active ingredients after thorough examinations. Because especially when antibiotics are used in large quantities, the likelihood of pathogens developing resistance increases.
On the sidelines of the UN General Assembly in New York, the “High Level Meeting on Antimicrobial Resistance” took place in September 2016, aimed at the global fight against antibiotic resistance. Representatives from politics, international organizations and industry discussed under the leadership of UN Secretary General Ban Ki-moon about approaches and solutions to eliminate multi-resistant germs in hospitals and to prevent antibiotic resistance. A draft political declaration on antibiotic resistance ("Draft political declaration of the high-level meeting of the General Assembly on antimicrobial resistance") was adopted, which calls for a cross-sectoral approach that takes into account human and animal health and an intact environment. The fight against antibiotic resistance should take place regionally, nationally and internationally with cross-border cooperation between government and non-governmental organizations (NGOs) and industry.
According to the Surveillance Atlas of Infectious Diseases , published (as of 2020) by the European Center for Disease Prevention and Control , antibiotic resistance is problematic in Greece at 63.9%, followed by Romania with 29.5% and Italy with 26 ,8th %. In Germany it is very low at 0.4%. The EU Commission sees antibiotic resistance as a threat to public health in Europe and is concerned about the high use of antibiotics in the EU member states. She wants to take action against the spread of multi-resistant germs.
So-called power amplifiers or mast accelerators have been banned throughout the EU since 2006. Infections in cattle can still be treated with antibiotics, but this is also necessary for animal welfare reasons. However, slaughter may only take place after a certain waiting period during which the animal has broken down the medication.
On October 25, 2018, the European Parliament passed a new regulation that restricts the use of antibiotics in livestock farming. It provides that
- certain antibiotics (so-called reserve antibiotics) are only reserved for humans, i.e. may no longer be administered in animal husbandry,
- a preventive intake of antibiotics is only allowed in exceptional cases, which must be justified by a veterinarian
- and antibiotics may no longer be used to fatten the animals. This means that animal feeds enriched with antibiotics are no longer allowed to be imported.
The regulation has yet to be formally adopted by the Council of Member States before publication in the Official Journal. The EU states then have three years to implement the new regulations. The regulation will therefore not take effect before the end of 2021.
Obligation to report on delivery and use in animals
Since 2011, pharmaceutical companies and wholesalers have had to report the quantities of antibiotics they dispense annually to veterinary pharmacies to a veterinary medicinal product register, broken down by region. This is intended to identify possible connections between the use of antibiotics and the development tendencies of resistance.
The 16th amendment to the Medicines Act (AMG) came into force in April 2014 . Since then, keepers of beef cattle, pigs, chickens and turkeys have been obliged to report antibiotic use to a nationwide veterinary medicinal product / antibiotic database (TAM) in accordance with AMG , provided that the statutory lower limits are exceeded . In addition, if there is a high frequency of therapy, animal owners must work with their veterinarian to develop a concept for reducing the amount of antibiotics administered, which is adapted to the respective operational requirements.
German Antibiotic Resistance Strategy (DART)
The German Antibiotic Resistance Strategy 2020 was adopted in May 2015 . The aim is to prevent the spread and development of resistances, as well as to promote research and development on the subject.
In October 2015, a declaration on combating antibiotic resistance was adopted at the G7 health ministerial meeting.
In the Netherlands, the authorities do not rely on sanctions. Exemplary farmers are to receive a bonus there in the future.
According to the Dutch veterinary authority, it has succeeded in halving the use of antibiotics in the country over the past five years.
Strategy for Antibiotic Resistance Switzerland (StAR)
On November 18, 2015, the Federal Council adopted the national strategy against antibiotic resistance (StAR).
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