Antibiotic resistance is the resistance of microbes to antimicrobial drugs. Bacteria should be considered resistant if they are not neutralized by such concentrations of the drug that are actually created in the macroorganism. Resistance can be natural or acquired.
Natural stability. Some types of microbes are naturally resistant to certain families of antibiotics, either as a result of the lack of an appropriate target (for example, mycoplasmas do not have a cell wall, so are not sensitive to all drugs acting at that level), or as a result of bacterial impermeability to a given drug (for example, gram-negative microbes less permeable to large molecular compounds than gram-positive bacteria, since their outer membrane has “small” pores).
Acquired resistance. The acquisition of resistance is a biological pattern associated with the adaptation of microorganisms to environmental conditions. It is true, although to varying degrees, for all bacteria and all antibiotics. Not only bacteria, but also other microbes - from eukaryotic forms (protozoa, fungi) to viruses - adapt to chemotherapy drugs. The problem of the formation and spread of drug resistance in microbes is especially significant for nosocomial infections caused by so-called “hospital strains”, which, as a rule, have multiple resistance to antibiotics (the so-called multiresistance).
Genetic basis of acquired resistance. Antibiotic resistance is determined and maintained by resistance genes (r-genes) and conditions that promote their spread in microbial populations. Acquired drug resistance can arise and spread through a bacterial population as a result of:
- * mutations in the chromosome of a bacterial cell with subsequent selection (i.e. selection) of mutants. Selection occurs especially easily in the presence of antibiotics, since under these conditions the mutants gain an advantage over other cells of the population that are sensitive to the drug. Mutations occur regardless of the use of the antibiotic, i.e. the drug itself does not affect the frequency of mutations and is not their cause, but serves as a selection factor. The resistant cells then produce offspring and can be transmitted to the body of the next host (human or animal), forming and spreading resistant strains. Mutations can be: 1) single (if the mutation occurred in one cell, as a result of which altered proteins are synthesized in it) and 2) multiple (a series of mutations, as a result of which not one, but a whole set of proteins changes, for example, penicillin-binding proteins in penicillin-resistant pneumococcus);
- * transfer of transmissible resistance plasmids (R-plasmids). Resistance (transmissible) plasmids usually encode cross-resistance to several families of antibiotics. For the first time, such multiple resistance was described by Japanese researchers in relation to intestinal bacteria. It has now been shown that it occurs in other groups of bacteria. Some plasmids can be transferred between bacteria of different species, so the same resistance gene can be found in bacteria that are taxonomically distant from each other. For example, beta-lactamase, encoded by plasmid TEM-1, is widespread in Gram-negative bacteria and is found in Escherichia coli and other enteric bacteria, as well as in penicillin-resistant gonococcus and ampicillin-resistant Haemophilus influenzae;
- * transfer of transposons carrying r-genes (or migrating genetic sequences). Transposons can migrate from a chromosome to a plasmid and back, as well as from a plasmid to another plasmid. In this way, resistance genes can be passed on to daughter cells or through recombination to other recipient bacteria.
Implementation of acquired stability. Changes in the genome of bacteria lead to changes in some properties of the bacterial cell, as a result of which it becomes resistant to antibacterial drugs. Typically, the antimicrobial effect of a drug is achieved in this way: the agent must bind to the bacterium and pass through its membrane, then it must be delivered to the site of action, after which the drug interacts with intracellular targets. The implementation of acquired drug resistance is possible at each of the following stages:
- * target modification. The target enzyme can be changed in such a way that its functions are not impaired, but the ability to bind to the chemotherapy drug (affinity) is sharply reduced or a “bypass” of metabolism can be turned on, i.e., another enzyme is activated in the cell that is not affected by the drug .
- * “inaccessibility” of the target due to a decrease in the permeability of the cell wall and cell membranes or the “effluent mechanism”, when the cell seems to “push” the antibiotic out of itself.
- * inactivation of the drug by bacterial enzymes. Some bacteria are capable of producing special enzymes that render drugs inactive (for example, beta-lactamases, aminoglycoside-modifying enzymes, chloramphenicol acetyltransferase). Beta-lactamases are enzymes that destroy the beta-lactam ring to form inactive compounds. The genes encoding these enzymes are widespread among bacteria and can be found either on a chromosome or on a plasmid.
To combat the inactivating effect of beta-lactamases, inhibitor substances are used (for example, clavulanic acid, sulbactam, tazobactam). These substances contain a beta-lactam ring and are able to bind to beta-lactamases, preventing their destructive effect on beta-lactams. However, the intrinsic antibacterial activity of such inhibitors is low. Clavulanic acid inhibits most known beta-lactamases. It is combined with penicillins: amoxicillin, ticarcillin, piperacillin.
It is almost impossible to prevent the development of antibiotic resistance in bacteria, but it is necessary to use antimicrobial drugs in such a way as not to contribute to the development and spread of resistance (in particular, use antibiotics strictly according to indications, avoid their use for prophylactic purposes, change antibiotic therapy after 10-15 days drug, if possible, use narrow-spectrum drugs, limit the use of antibiotics in veterinary medicine and do not use them as a growth factor). No. 45 Methods for determining the sensitivity of bacteria to antibiotics.
To determine the sensitivity of bacteria to antibiotics (antibioticograms), the following are usually used:
- *Agar diffusion method. The microbe under study is inoculated onto an agar nutrient medium, and then antibiotics are added. Typically, drugs are added either to special wells in agar, or discs with antibiotics are placed on the surface of the inoculation (“disc method”). The results are recorded every other day based on the presence or absence of microbial growth around the holes (discs). The disk method is qualitative and allows you to assess whether the microbe is sensitive or resistant to the drug.
- * Methods for determining minimum inhibitory and bactericidal concentrations, i.e. the minimum level of an antibiotic that allows in vitro to prevent the visible growth of microbes in a nutrient medium or completely sterilize it. These are quantitative methods that allow you to calculate the dose of the drug, since the concentration of the antibiotic in the blood must be significantly higher than the minimum inhibitory concentration for the infectious agent. Administration of adequate doses of the drug is necessary for effective treatment and prevention of the formation of resistant microbes.
There are accelerated methods using automatic analyzers.
Determination of bacterial sensitivity to antibiotics using the disc method. The bacterial culture under study is inoculated onto nutrient agar or AGV medium in a Petri dish.
AGV medium: dry nutrient fish broth, agar-agar, disodium phosphate. The medium is prepared from dry powder in accordance with the instructions.
Paper discs containing certain doses of different antibiotics are placed on the inoculated surface with tweezers at equal distances from each other. The crops are incubated at 37 °C until the next day. The diameter of the zones of growth inhibition of the studied bacterial culture is used to judge its sensitivity to antibiotics.
To obtain reliable results, it is necessary to use standard disks and nutrient media, for control of which reference strains of the relevant microorganisms are used. The disk method does not provide reliable data when determining the sensitivity of microorganisms to polypeptide antibiotics that diffuse poorly into agar (for example, polymyxin, ristomycin). If these antibiotics are intended to be used for treatment, it is recommended to determine the sensitivity of microorganisms by serial dilution.
Determination of bacterial sensitivity to antibiotics by serial dilution method. This method determines the minimum concentration of the antibiotic that inhibits the growth of the test bacterial culture. First, prepare a stock solution containing a certain concentration of antibiotic (µg/ml or IU/ml) in a special solvent or buffer solution. All subsequent dilutions in broth (in a volume of 1 ml) are prepared from it, after which 0.1 ml of the test bacterial suspension containing 106-107 bacterial cells in 1 ml is added to each dilution. Add 1 ml of broth and 0.1 ml of bacterial suspension (culture control) to the last test tube. The crops are incubated at 37 °C until the next day, after which the results of the experiment are noted by the turbidity of the nutrient medium, comparing with the culture control. The last test tube with a transparent nutrient medium indicates a retardation of the growth of the bacterial culture under study under the influence of the minimum inhibitory concentration (MIC) of the antibiotic contained in it.
The results of determining the sensitivity of microorganisms to antibiotics are assessed using a special ready-made table, which contains the boundary values of the diameters of growth inhibition zones for resistant, moderately resistant and sensitive strains, as well as the MIC values of antibiotics for resistant and sensitive strains.
Sensitive strains include strains of microorganisms whose growth is inhibited at concentrations of the drug found in the patient’s blood serum when using normal doses of antibiotics. Moderately resistant strains are those whose growth inhibition requires concentrations created in the blood serum upon administration of maximum doses of the drug. Resistant are microorganisms whose growth is not suppressed by the drug in concentrations created in the body when using the maximum permissible doses.
Determination of antibiotics in blood, urine and other fluids of the human body. Two rows of test tubes are placed in a rack. In one of them, dilutions of the standard antibiotic are prepared, in the other, dilutions of the test liquid are prepared. Then a suspension of test bacteria prepared in Hiss medium with glucose is added to each test tube. When determining penicillin, tetracyclines, and erythromycin in the test liquid, the standard strain of S. aureus is used as test bacteria, and when determining streptomycin, E. coli is used. After incubating the crops at 37 °C for 18-20 hours, the results of the experiment are noted by the turbidity of the medium and its staining with an indicator due to the breakdown of glucose by test bacteria. The concentration of the antibiotic is determined by multiplying the highest dilution of the test liquid, which inhibits the growth of test bacteria, by the minimum concentration of the reference antibiotic, which inhibits the growth of the same test bacteria.
For example, if the maximum dilution of the test liquid that inhibits the growth of test bacteria is 1:1024, and the minimum concentration of the reference antibiotic that inhibits the growth of the same test bacteria is 0.313 μg/ml, then the product 1024 - 0.313 = 320 μg/ml is the concentration antibiotic in 1 ml.
Determination of the ability of S. aureus to produce beta-lactamase. In a flask with 0.5 ml of a daily broth culture of a standard strain of staphylococcus sensitive to penicillin, add 20 ml of melted and cooled to 45 ° C nutrient agar, mix and pour into a Petri dish. After the agar has solidified, a disk containing penicillin is placed in the center of the plate on the surface of the medium. The crops under study are sown in a loop along the radii of the disk. The crops are incubated at 37 °C until the next day, after which the results of the experiment are noted. The ability of the studied bacteria to produce beta-lactamase is judged by the presence of growth of a standard strain of staphylococcus around one or another test culture (around the disk). No. 46 Principles of rational antibiotic therapy.
Prevention of the development of complications consists primarily of following the principles of rational antibiotic therapy (antimicrobial chemotherapy):
* Microbiological principle. Before prescribing the drug, the causative agent of the infection should be identified and its individual sensitivity to antimicrobial chemotherapeutic drugs should be determined. Based on the results of the antibiogram, the patient is prescribed a narrow-spectrum drug that has the most pronounced activity against a specific pathogen, at a dose 2-3 times higher than the minimum inhibitory concentration. If the causative agent is still unknown, then drugs of a wider spectrum are usually prescribed, active against all possible microbes that most often cause this pathology.
Correction of treatment is carried out taking into account the results of bacteriological examination and determination of the individual sensitivity of a particular pathogen (usually after 2-3 days). You need to start treating the infection as early as possible (firstly, at the beginning of the disease there are fewer microbes in the body, and secondly, the drugs have a more active effect on growing and multiplying microbes).
- * Pharmacological principle. The characteristics of the drug are taken into account - its pharmacokinetics and pharmacodynamics, distribution in the body, frequency of administration, the possibility of combining drugs, etc. Doses of drugs must be sufficient to ensure microbostatic or microbicidal concentrations in biological fluids and tissues. It is necessary to understand the optimal duration of treatment, since clinical improvement is not a reason to discontinue the drug, because pathogens may persist in the body and there may be a relapse of the disease. The optimal routes of drug administration are also taken into account, since many antibiotics are poorly absorbed from the gastrointestinal tract or do not penetrate the blood-brain barrier.
- * Clinical principle. When prescribing a drug, they take into account how safe it will be for a given patient, which depends on the individual characteristics of the patient’s condition (severity of infection, immune status, gender, pregnancy, age, state of liver and kidney function, concomitant diseases, etc.) In severe cases In life-threatening infections, timely antibiotic therapy is of particular importance. Such patients are prescribed combinations of two or three drugs to ensure the widest possible spectrum of action. When prescribing a combination of several drugs, you should know how effective the combination of these drugs will be against the pathogen and how safe for the patient it will be, i.e., so that there is no antagonism of the drugs in relation to antibacterial activity and there is no summation of their toxic effects.
- * Epidemiological principle. The choice of drug, especially for an inpatient, should take into account the resistance status of microbial strains circulating in a given department, hospital, and even region. It should be remembered that antibiotic resistance can not only be acquired, but also lost, while the natural sensitivity of the microorganism to the drug is restored. Only natural stability does not change.
- * Pharmaceutical principle. It is necessary to take into account the expiration date and follow the rules for storing the drug, since if these rules are violated, the antibiotic can not only lose its activity, but also become toxic due to degradation. The cost of the drug is also important.
Drug resistance of microorganisms the ability of microorganisms to maintain vital activity, including despite contact with chemotherapy drugs. () microorganisms are distinguished by their tolerance, in which microbial cells do not die in the presence of chemotherapy drugs due to a reduced amount of autolytic enzymes, but also do not multiply. L.u.m. - a widespread phenomenon that interferes with the treatment of infectious diseases. The most studied bacteria. There are drug resistance that is naturally inherent in microorganisms and that arises as a result of mutations or the acquisition of foreign genes. Natural L.s.m. is caused by the absence of a target for chemotherapy drugs in the microbial cell or the impermeability of the microbial cell membrane to them. It is characteristic, as a rule, of all representatives of a given species (sometimes genus) of bacteria in relation to a specific group of chemotherapy drugs. Examples include the resistance of mycoplasmas to penicillin due to their lack of a cell wall and the enzymes of its synthesis - targets for penicillin, as well as the resistance of Pseudomonas aeruginosa to erythromycin due to the inability of the latter to penetrate through its membrane to its targets, the ribosomes. Drug resistance of microorganisms as a result of mutations or the acquisition of foreign genes by representatives of species that are initially sensitive to specific chemotherapy drugs has become widespread due to the selective background created by widely used drugs for the survival of specifically resistant forms of bacteria. Thus, the frequency of detection of penicillin-resistant staphylococci in some regions reaches 80-90%, streptomycin-resistant - 60-70%, ampicillin-resistant shigella - 90%, tetracycline and streptomycin resistant - more than 50%, etc. Depending on the location in the chromosome or plasmid of the genes that determine resistance, it is customary to distinguish between L.m. of chromosomal and plasmid origin. However, plasmid genes can be included in a chromosome, chromosomal genes can be found in a replicon. This is due to the presence of transposons - genetic elements capable of transitioning in a cell from one replicon to another. The exchange of genetic material in bacteria through conjugation and transduction contributes to the rapid spread of resistance genes between strains of the same species (less commonly, genus). Selective, created by a number of constantly used antibiotics, can lead to the inclusion of several genes for resistance to various chemotherapy drugs in the plasmid. Due to this, so-called multiresistant strains of bacteria arise. A plasmid replicon may simultaneously contain several genes that confer resistance to one antimicrobial agent, but through different mechanisms. Genes associated with resistance to a particular antimicrobial agent can have both chromosomal and plasmid localization in the same cell, encoding different mechanisms of resistance. Drug resistance of microorganisms is often inducible, i.e. expression of resistance genes occurs only after cell contact with an antimicrobial agent. An example of this is the frequent occurrence of the formation of an inactivating enzyme after contact of a bacterial culture with a beta-lactam antibiotic. Drug resistance of microorganisms is due to the following main mechanisms: enzymatic inactivation of the antimicrobial agent, weakening of its penetration into the pathogen cell, changes in the conformation of the intracellular target for the antimicrobial agent, which prevents its interaction with the target, the formation of an increased number of target molecules on which the antimicrobial agent acts. Representatives of hydrolases are known as inactivating enzymes - beta-lactamases, which catalyze the beta-lactam ring in penicillins, cephalosporins and other beta-lactams (monobactams, carbapenems, etc.), as well as esterases, which act on some other structures close to it . Another group of inactivating enzymes is . These include chloramphenicol-(chloramphenicol-)-acetyltransferases, aminoglycoside acetyl, phospho- or adenylyltransferases and those acting on erythromycin. Beta-lactamases are produced by many gram-positive and gram-negative bacteria. Encoded by both chromosomal and plasmid genes. There are several classification systems for beta-lactamases, based on their substrate specificity, sensitivity to inhibitors, isoelectric point and other indicators. beta-lactamases to penicillinases and cephalosporinases are largely conditional. Beta-lactamases of gram-positive bacteria, as a rule, are released into the external environment, while gram-negative bacteria are contained in the cytoplasmic membrane and periplasmic space (under the outer membrane). Beta-lactamases of both chromosomal and plasmid origin can be present in one cell. Transferases catalyze the reaction of replacing a functional group of an antibiotic with an acetic, phosphoric or adenylic acid residue. When using aminoglycoside antibiotics, substitution of amino groups (N-acetalation) and hydroxyl groups (O-phosphorylation and O-adenylation) has been described. One usually affects one functional group. O-phosphorylation of chloramphenicol and erythromycin has also been described. Antibiotics that have undergone modifications lose . Transferases can play a protective role only in the presence of (donor phosphoric or adenylic acid residue) or coenzyme A (donor acetyl residue), so their protective role is lost when transferred to the external environment. In most cases, they are not released from the cell. The permeability of the bacterial cell membrane to chemotherapy drugs weakens as a result of a decrease in the number of porin proteins and the water channels they form in the outer membrane through which drugs diffuse. Such a L.u.m mechanism can be realized in relation to beta-lactams, amino-glycosides, fluoroquinolones, etc. Antimicrobial agents with pronounced hydrophobicity (some of the penicillins, fluoroquinolones, etc.) penetrate the cell through the lipid regions of the outer membrane. Changes in the structure of lipids can affect L.m. Some antibiotics, for example, penetrate through the cytoplasmic membrane using energy-dependent specific transport systems. In the absence of functioning cytochrome electron transport systems, the transfer of aminoglycosides into the cell stops. This explains the sharp drop in the activity of aminoglycosides under anaerobic conditions and the natural resistance of anaerobes to them. The mechanism of tetracycline resistance is associated with changes in the cell membrane. Due to membrane TET proteins encoded by chromosomal or plasmid genes, in this case, as a rule, there is a rapid elimination of tetracycline molecules that have penetrated into the cell, which do not have time to react with their target - the ribosome. Resistance to the antibiotic vancomycin is associated with the appearance of proteins in the cytoplasmic membrane that shield, i.e. making inaccessible to it are the peptide chains of peptidoglycan, with which it reacts during the assembly of this polymer. A change in target conformation is often observed when microorganisms are resistant to beta-lactams, fluoroquinolones, and other chemotherapy drugs. biosynthesis of bacterial cell wall peptidoglycan - transpeptadase and D 1 D-carboxypeptidase (so-called penicillin-binding) stop binding beta-lactams when the conformation changes, and DNA gyrase (the target for fluoroquinolones) stops reacting with these chemotherapy drugs. Resistance to aminoglycosides may be due to a decrease in their binding to ribosomes as a result of changes in the conformation of individual ribosomal proteins. Resistance to erythromycin at the level of its target (ribosomes) is due to specific ribosomal methylation in the large ribosomal subunit. This leads to the prevention of the reaction of erythromycin with ribosomes. An increased number of target molecules in the cell and, as a result, resistance to the antimicrobial agent were observed with resistance to trimethoprim, caused by increased formation of folic acid reductase. The selection and widespread spread of antibiotic-resistant bacteria is facilitated by the irrational and unjustified use of antibiotics. The resistance of microorganisms may be associated with the growth phase of pathogens at the site of inflammation, when their number reaches 10 8 -
10 9 individuals in 1 ml homogenized sample of the test material. In this phase, microbial cells cease, and the pathogen becomes indifferent or less sensitive to the inhibitory effects of many antimicrobial drugs. Known difficulties in chemotherapy are caused by L-forms of bacteria, which differ in sensitivity from the original bacteria with a normal cell wall. Pathogens can be resistant to antimicrobial drugs in cases of their association with bacteria that inactivate these drugs. The activity of antibiotics is also influenced by the pH value of the environment, the degree of anaerobiosis, the presence of foreign substances, the state of nonspecific resistance and immunity factors, and interdrug interactions. The mechanisms of drug resistance of fungi and protozoa have features associated with the structural organization and chemical composition of their cells. It has been noted that the resistance of fungi to polyenes (nystatin, amphotericin B, etc.) that react with sterols of the cytoplasmic membrane increases slightly with a decrease in the amount of sterols in the membrane or as a result of changes in the molecular organization of the membrane, leading to a decrease in the contact of the polyene with sterols. The drug resistance of viruses has been poorly studied. It has been shown that when nucleosides are used as antiviral agents, resistance may be associated with mutations in the viral thymidine kinase genes or DNA polymers .
Thus, resistance to idoxuridine may occur in keratitis caused by herpes simplex viruses. In mutants of the herpes simplex virus. resistant to vidarabine, the DNA polymerase gene is altered. The conclusion about the sensitivity or resistance of microorganisms is made based on determining the size of the zone of suppression of their growth on a dense nutrient medium around disks impregnated with antimicrobial agents (disc diffusion method). Antimicrobial drugs are also used in solid and liquid nutrient media (see Microbiological diagnostics); antiviral drugs are determined using methods of cultivating viruses in cell culture. chicken embryos or laboratory animals. Overcoming L.u.m is achieved in various ways: by introducing so-called loading doses of antimicrobial drugs that can suppress the growth of relatively resistant microorganisms, by continuing treatment using sufficiently high doses of drugs and by following the recommended regimen. Changing the antibiotics used in the clinic and combining them are very effective in the fight against drug-resistant microorganisms. But, for example, when a bacteriostatic antibiotic is combined with a bactericidal one (chloramphenicol with penicillin), interdrug antagonism is possible, leading to a weakening of the antimicrobial effect. To protect beta-lactam antibiotics from bacterial beta-lactamases, inhibitors of these enzymes are used - clavulanic acid, sulbactam (penicillanic acid sulfone), etc. The discovery of clavulanic acid, which contains a beta-lactam ring and blocks a number of beta-lactamases, stimulated the search for various enzyme inhibitors ( analogues of substrates), which makes it possible to significantly expand the use of antibiotics that are sensitive to the enzymes that inactivate them. A search is also underway for new natural antibiotics and chemical modification of already known antibiotics in order to obtain antimicrobial substances effective against bacteria that are resistant to drugs already used. Systematic identification of drug-resistant microorganisms and timely information about drug resistance phenotypes circulating in these regions make it possible to guide the doctor towards the use of the most suitable drug in terms of the spectrum of action and the most favorable combinations of drugs, of course taking into account their possible incompatibility (see Incompatibility of drugs) .
As growth stimulants for agricultural products. animals, veterinary medicine, and crop production, it is advisable not to use antibiotics used in the clinic and causing cross-resistance to medical antibiotics. Bibliography: Briand L.E. Bacterial resistance and sensitivity to chemotherapy. from English, M., 1984; Lancini D. and Parenti F., trans. from English, p. 89. M., 1985; Navashin S.M. and Fomina I.P. Rational, p. 25, M., 1982; Franklin T. and Snow J. antimicrobial action, translated from English, p. 197, M., 1984.
1. Small medical encyclopedia. - M.: Medical encyclopedia. 1991-96 2. First aid. - M.: Great Russian Encyclopedia. 1994 3. Encyclopedic Dictionary of Medical Terms. - M.: Soviet Encyclopedia. - 1982-1984.
- - extrachromosomal (additional to the chromosome) genetic structures of bacteria, capable of autonomously multiplying and existing in the cytoplasm of a bacterial cell. Some plasmids can turn on at a certain frequency... ... Medical encyclopedia
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Microbial resistance to antibiotics
With the discovery of antibiotics that have a selective effect on microbes in vivo (in the body), it might seem that the era of man's final victory over infectious diseases has arrived. But soon the phenomenon of resistance (resistance) of individual strains of pathogenic microbes to the destructive effects of antibiotics was discovered. As the duration and scale of practical use of antibiotics increased, the number of resistant strains of microorganisms also increased. If in the 40s clinicians had to deal with isolated cases of infections caused by resistant forms of microbes, now the number, for example, of staphylococci resistant to penicillin, streptomycin, chloramphenicol (chloramphenicol) exceeds 60-70%. What explains the phenomenon of antibiotic resistance?
The resistance of microorganisms to the action of antibiotics is caused by several reasons. Basically they boil down to the following. Firstly, in any collection of microorganisms that coexist on a particular area of the substrate, naturally antibiotic-resistant variants are found (about one individual per million). When a population is exposed to an antibiotic, the majority of cells die (if the antibiotic has a bactericidal effect) or stop developing (if the antibiotic has a bacteriostatic effect). At the same time, single cells resistant to the antibiotic continue to multiply unhindered. Antibiotic resistance by these cells is inherited, giving rise to a new antibiotic-resistant population. In this case, selection (selection) of resistant variants occurs using an antibiotic. Secondly, antibiotic-sensitive microorganisms may undergo a process of adaptation (adaptation) to the harmful effects of the antibiotic substance. In this case, there may be, on the one hand, a replacement of some links in the microorganism's metabolism, the natural course of which is disrupted by the antibiotic, with other links that are not affected by the drug. In this case, the microorganism will also not be suppressed by the antibiotic. On the other hand, microorganisms can begin to intensively produce substances that destroy the antibiotic molecule, thereby neutralizing its effect. For example, a number of strains of staphylococci and spore-bearing bacteria produce the enzyme penicillinase, which destroys penicillin to form products that do not have antibiotic activity. This phenomenon is called enzymatic inactivation of antibiotics.
It is interesting to note that penicillinase has now found practical use as an antidote - a drug that removes the harmful effects of penicillin when it causes severe allergic reactions that threaten the patient's life.
Microorganisms that are resistant to one antibiotic are simultaneously resistant to other antibiotic substances that are similar to the first in their mechanism of action. This phenomenon is called cross-resistance. For example, microorganisms that become resistant to tetracycline simultaneously become resistant to chlortetracycline and oxytetracycline.
Finally, there are strains of microorganisms that contain so-called R-factors, or resistance factors (resistance) in their cells. The spread of R-factors among pathogenic bacteria to the greatest extent reduces the effectiveness of treatment with many antibiotics compared to other types of microbial resistance, since it causes resistance to several antibacterial substances simultaneously.
All these facts suggest that for successful treatment with antibiotics, it is necessary to determine the antibiotic resistance of pathogenic microbes before prescribing them, and also try to overcome the drug resistance of microbes.
The main ways to overcome microbial resistance to antibiotics, which reduces the effectiveness of treatment, are as follows:
research and implementation of new antibiotics, as well as the production of derivatives of known antibiotics;
the use for treatment of not one, but simultaneously several antibiotics with different mechanisms of action; in these cases, various metabolic processes of the microbial cell are simultaneously suppressed, which leads to its rapid death and greatly complicates the development of resistance in microorganisms; the use of a combination of antibiotics with other chemotherapy drugs. For example, the combination of streptomycin with para-aminosalicylic acid (PAS) and ftivazid dramatically increases the effectiveness of treatment of tuberculosis;
suppression of the action of enzymes that destroy antibiotics (for example, the action of penicillinase can be suppressed with crystal violet);
freeing resistant bacteria from multidrug resistance factors (R factors), for which certain dyes can be used.
There are many conflicting theories that attempt to explain the origin of drug resistance. They mainly concern questions about the role of mutations and adaptation in the acquisition of resistance. Apparently, in the process of developing resistance to drugs, including antibiotics, both adaptive and mutational changes play a certain role.
Nowadays, when antibiotics are widely used, forms of microorganisms resistant to antibiotics are very common.
Life of plants: in 6 volumes. - M.: Enlightenment. Edited by A. L. Takhtadzhyan, editor-in-chief, corresponding member. USSR Academy of Sciences, prof. A.A. Fedorov. 1974 .
See what “Resistance of microorganisms to antibiotics” is in other dictionaries:
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Ov; pl. (unit antibiotic, a; m.) [from Greek. anti against and bios life]. Substances of biological origin that can suppress the activity of pathogenic microorganisms. Take a. Strong a. * * * antibiotics (from anti... and Greek bíos ... ... encyclopedic Dictionary
Mechanisms of drug resistance formation.
~ enzymatic inactivation of antibiotic
~ change in the structure of the target for the antibiotic
~ hyperproduction of the target (change in the agent-target ratio)
~ active release of antibiotic from a microbial cell
~ change in cell wall permeability
~ enabling a “metabolic shunt” (metabolic bypass)
Variants of drug resistance of MBT.
Monoresistance– resistance to one anti-tuberculosis drug (ATD).
Multidrug resistance- this is the resistance of MBT to any two or more anti-TB drugs without simultaneous resistance to isoniazid and rifampicin.
Multidrug resistance (MDR)– resistance to the action of isoniazid and rifampicin simultaneously, with or without resistance to other anti-TB drugs. These strains of Mycobacterium tuberculosis are given special attention, since the treatment of patients in whom the process is caused by such strains is very difficult. It is lengthy, expensive and requires the use of backup drugs, many of which are expensive and can cause severe adverse reactions. In addition, multidrug-resistant strains cause severe, progressive forms of the disease, often leading to adverse outcomes.
Extensively drug resistant (XDR, XDR, extreme DR)- this is the simultaneous resistance of MBT to isoniazid, rifampicin, injectable aminoglycosides and fluoroquinolones.
Total drug resistance– resistance to all anti-traffic drugs.
Cross drug resistance– this is a situation where resistance to one anti-inflammatory drug entails resistance to other anti-inflammatory drugs. Cross-LN is especially often observed within the group of aminoglycosides.
Methods for determining MBT DR.
Determining the spectrum and degree of resistance of mycobacteria to anti-tuberculosis drugs is important for the tactics of chemotherapy for patients, monitoring the effectiveness of treatment, determining the prognosis of the disease and conducting epidemiological monitoring of drug resistance of mycobacteria within a particular territory, country and world community. The degree of drug resistance of mycobacteria is determined in accordance with established criteria, which depend both on the antituberculosis activity of the drug and its concentration in the lesion, the maximum therapeutic dose, the pharmacokinetics of the drug and many other factors.
The cultural method makes it possible to determine the sensitivity and resistance of MBT to anti-tuberculosis antibiotics. The most common method for determining the drug resistance of mycobacteria must be carried out on a solid Lowenstein-Jensen nutrient medium.
All methods for determining drug resistance are divided into two groups:Currently, the following methods are used in international practice to determine the drug sensitivity of mycobacteria to anti-tuberculosis drugs:
- method of proportions on Lowenstein-Jensen medium or Middlebrook 7N10 medium
- method of absolute concentrations on dense egg medium of Levenstein-Jensen
- resistance coefficient method
- radiometric method Bactec 460/960, as well as other automatic and semi-automatic systems
- molecular genetic methods for detecting mutations (TB biochips, GeneXpert)
Absolute concentration method in most cases used for indirect determination of drug resistance. The results of determining drug resistance using the specified method on Lowenstein-Jensen medium are usually obtained no earlier than 2 - 2.5 months after inoculation of the material. The use of the “Novaya” nutrient medium can significantly reduce these times.
For the absolute concentration method, the appearance more than 20 CFU mycobacteria on a nutrient medium containing the drug in a critical concentration, indicates that this strain of mycobacteria has drug resistance.
A culture is considered sensitive to a given concentration of the drug if less than 20 small colonies grow in a test tube with a medium containing the drug, with abundant growth in the control tube.
A culture is considered resistant to the concentration of the drug contained in a given test tube if more than 20 colonies have grown in the test tube with the medium (“confluent growth”) with abundant growth in the control.
Method of proportions. The method is based on comparing the number of mycobacteria from an isolated culture that grew in the absence of the drug and in its presence at critical concentrations. To do this, the prepared suspension of mycobacteria is diluted to a concentration of 10 -4 and 10 -6. Both dilutions of the suspension are inoculated onto a nutrient medium without the drug and onto a set of media with different drugs. If colonies grow on the medium with the drug that are more than 1% of the number grown on the medium without the drug, the culture is considered resistant to this drug. If the number of CFU resistant to this drug is less than 1%, the culture is considered sensitive.
Resistance coefficient method. This method is based on determining the ratio of the minimum inhibitory concentration (MIC) determined for a given strain of a particular patient to the MIC of a drug-sensitive standard strain N 37 Rv tested in the same experiment. In this case, the strain N 37 Rv is not used to control the experiment, but to determine possible variations when setting up the test. From this point of view, this method is the most accurate of the three listed above, however, due to the need to use a large number of test tubes with a nutrient medium, it is also the most expensive. The latter circumstance sharply limits its use.
VASTES system. For this method, absolute concentrations of drugs in the prepared liquid nutrient medium are used. The results are recorded automatically.
The long history and widespread use of antibiotics, violations in the correct use, without taking into account sensitivity, indications, widespread use in the national economy - livestock farming, crop production, food industry - has given rise to a new complex problem - drug resistance of microorganisms. Resistance of microorganisms can be either natural or congenital, or acquired.
True (natural congenital primary) resistance is characterized by the absence of antibiotic action in target microorganisms or the inaccessibility of the target due to primary low permeability or enzymatic inactivation. Natural resistance is a constant species characteristic of microorganisms and is easily predicted. An example is the absence of a cell wall in mycoplasmas.
Acquired resistance– the property of individual strains of bacteria to remain viable at those concentrations of antibiotics that suppress the main part of the microbial population, acquired as a result of gene mutation, recombination, etc.
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 main mechanism of secondary resistance is the acquisition of resistance genes (r-genes) carried by transposons and plasmids.
It is important to remember that ABs do not contribute to the formation of these plasmids, but only help evolution (selection factor)
The following biochemicals are known mechanisms of antibiotic resistance in bacteria:
1. Modification of the target of action (change in structure)
2. Antibiotic inactivation
3. Active removal of antibiotics from microbial cells
4. Violation of the permeability of the external structures of the microbial cell
5. Formation of a metabolic “shunt”
Modification (change in structure) of the action target– the targets of b-lactam antibiotics are enzymes involved in the synthesis of peptidoglycan. Changes in the structure of these enzymes as a result of mutations in the corresponding genes mean that antibiotics do not recognize and do not act directly on the target enzymes.
Antibiotic inactivation– enzymatic. b-lactamases are found in the vast majority of clinically significant microorganisms. As a result of hydrolysis of one of the bonds of the b-lactam ring, the antibiotic is inactivated. The main mechanism of resistance to aminoglycosides is their enzymatic inactivation by modification. R-plasmids of microorganisms contain genes that can cause, for example, phosphorylation, acetylation of the antibiotic, as a result of which its structure changes and, as a rule, inactivation occurs. Modified aminoglycoside molecules lose their ability to bind to ribosomes and suppress protein biosynthesis.
Let us repeat once again that the secondary resistance of bacteria against penicillins and cephalosporins is associated with plasmid-dependent (much less often chromosomal) production of beta-lactamases - enzymes that destroy the active center of beta-lactam antibiotics. More than 100 beta-lactamases are known, but not all of them are involved in clinically significant bacterial resistance.
There are two type of beta-lactamase - penicillinase And cephalosporinases, which is quite arbitrary, since both of them attack both groups of antibiotics, although with different effectiveness. Gram-positive bacteria (eg, staphylococcus) usually produce extracellular beta-lactamases, which destroy drugs before contact with bacteria. They belong to the category inducible enzymes, and antibiotics themselves often act as an inducer. In such cases, increasing the dosage does not enhance the antibacterial effect, as it leads to overproduction of the inactivating enzyme.
In gram-negative bacteria beta-lactamases are concentrated in the periplasm or associated with the inner membrane . They are often constitutive, those. are produced at a constant level, which does not change under the influence of the antibiotic. Therefore, increasing the dosage sometimes helps overcome resistance. We can, for example, recall the treatment of gonorrhea: at first the gonococcus showed amazing sensitivity to benzylpenicillin, but over the past 30 years its dosage had to be constantly increased.
A notorious example of the rapid evolution of resistance to natural penicillins is Staphylococcus aureus. Without testing for sensitivity, any freshly isolated strain of Staphylococcus aureus today is recommended to be considered penicillin-resistant, which actually recognizes the species rank of this trait. But for other bacteria that were recently considered absolutely sensitive to beta-lactams, many exceptions have appeared. Penicillin-resistant strains occur among all gram-positive and gram-negative bacteria, although the example of catastrophically rapid development of beta-lactamase resistance is unique to staphylococcus. This may be due to the fact that in many bacteria resistance arose on a chromosomal (“immobile”) basis, and only later did strains with mobile r genes begin to dominate. In addition, beta-lactam antibiotics differ in their affinity for beta-lactamases. Some of them (penicillinase-resistant penicillins, 3rd generation cephalosporins, imipenem) are hydrolyzed by few beta-lactamases and (they are called beta-lactamase-resistant), while others (for example, ampicillin) are much more sensitive. There are antibiotics that are resistant against gram-negative beta-lactamases, but are destroyed by gram-positive bacteria (for example, temocillin).
To suppress the activity of beta-lactamases It is proposed to include their inhibitors in the composition of drugs - clavulanic acid and penicillanic acid sulfones (sulbactam, YTR-830, etc.). They belong to the beta-lactam family, but have weak antibiotic activity. At the same time, having a beta-lactam ring, they react excellently with beta-lactamases and, by intercepting them, prevent the destruction of “real” antibiotics. The enzyme and inhibitor can enter into a temporary relationship to form a fragile complex, but more often irreversible inactivation of the enzyme occurs. The range of beta-lactamases that can be inhibited is very wide, including the most common gram-positive and gram-negative beta-lactamases. It may seem strange that, having the opportunity to obtain stable monomolecular antibiotics (see above), they take the path of creating complex mixtures. But the fact is that the structural changes through which beta-lactamase resistance is achieved sometimes negatively affect the antibacterial and pharmacological properties of the drug (for example, the activity of penicillinase-resistant penicillins is 10-30 times lower than natural penicillin). Combination with inhibitors allows you to avoid this, using the advantages of “classical” beta-lactams.
Often the sources of r-plasmids are the normal microflora of the macroorganism.
Active removal of antibiotics from the cell– microorganisms have transport systems in the CPM, encoded by various genes, which carry out active selective removal of antibacterial drugs; antibiotics do not have time to reach their target.
Violation of the permeability of external structures– as a result of mutations, complete or partial loss of structures that carry out transport through the outer membrane is possible. For example, complete or partial loss of porin proteins, which transport substances across the cytoplasmic membrane.
Formation of a metabolic “shunt”- may be the result of the acquisition of new genes, as a result of which bacteria form “bypass” metabolic pathways for the biosynthesis of target enzymes that are insensitive to antibiotics.