ANTIBIOTICS (Greek anti-against +bios life) - the substances of a microbic, animal or plant origin which are selectively suppressing viability of microorganisms.
- 1 Istoiya
- 2 Classification of antibiotics
- 3 Semi-synthobiotics
- 4 the Mechanism of action of antibiotics
- 5 Receiving antibiotics
- 6 Use of antibiotics
- 7 Resistance of bacteria to antibiotics
- 8 TABLES (the annex to the article «Antibiotics»)
- 8.1 Table 1. Sensitivity of some microorganisms to antibiotics
- 8.2 Table 2. Priority of use of antibiotics at the purulent and inflammatory processes caused by bacteria
- 8.3 Table 3. Range of the minimum concentration of antibiotics (in vitro), overwhelming causative agents of infections
- 8.4 Table 4. Definition of a dose and way of introduction of the antibiotic providing the necessary level of its concentration in blood serum
- 8.5 Table 5. Approximate range of single doses, frequency of introduction and duration of use of antibiotics with the medical purpose depending on a way of introduction
- 9 Additional materials
- 9.1 Classification of antibiotics and their use
- 9.2 the Problem of resistance of microorganisms to antibiotics
- 9.3 The characteristic of the major groups of antibiotics
- 9.4 The principles of rational use of antibiotics
- 9.5 By-effects at use of antibiotics
- 9.6 Table. Range, mechanism and type of antimicrobic action of the main antibiotics and method of their introduction
the Term «antibiotics» is offered by S. A. Waksman in 1942.
The first attempts to use And. in the medical purposes H were made. N. Blagoveschensky in 1890. It showed that the pyocyanic stick suppresses development of a malignant anthrax in animals; at the same time medical action of a pyocyanic stick is caused by a certain waste product of this microbe, i.e. substance, a cut call an antibiotic now.
First attempts of allocation And. were made Emmerich (R. Emmerich, 1889) isolating from cultures of a pyocyanic stick substance, a cut he called a pyocyanase, having bactericidal properties concerning activators of a malignant anthrax, a typhoid, diphtheria, plague and stafilokokk. The pyocyanase was used a nek-swarm time for topical treatment of wounds. The received drug was not standard, and results of its use were very non-constant. Almost at the same time Η. F. Gamaley other low-toxic drug called pioklastiny, active concerning a number of microbes received from culture of a pyocyanic stick. In 1896 Mr. of Gozio (V. of Gosio) allocated from a mold (Penicillium) first crystal And. - mikofenovy to - that is and showed that this connection detained development of bacteria of a malignant anthrax. In 1924 Gratsia and Dates (A. Gratia, S. Dath) described the new antibiotic substance formed by Actinomyces albus, a cut they called aktinomitsetiny. In 1931 it was allocated And. tsitrinin from culture of Penicillium citrinum.
A milestone in researches A. Dyubo's works (R. J. Dubos, 1939) who received the crystal substance tyrothricin consisting of two antibiotics polypeptides from a soil bacterium of Bacillus brevis - gramicidin and tyrocidin are.
Gramicidin was more active concerning gram-positive, and tyrocidin - concerning gram-negative bacteria. Tyrothricin possesses strong bactericidal action in a test tube concerning many pathogenic microbes, having medical effect in experiences on the mice infected with a pneumococcus. It is the first And., really implemented in medical practice; it is applied quite widely and in a crust, time. Later, in 1942, to G.F. Gauza and M. G. Brazhnikov was allocated from a new kind of Bacillus brevis A., Dyubo called gramicidin C, having nek-ry advantages in comparison with tyrothricin.
A revolution in the doctrine about And. resulted from discovery of penicillin by A. Fleming. In 1929 Fleming observed that around colonies of Penicillium notatum of colony of staphylococcus in a Petri dish lyse, and filtrates of bouillon cultures of this mushroom possess antibacterial action concerning gram-positive and some gram-negative microbes (a gonokokka, a meningokokka). Florey and Cheyn was not succeeded to emit pure penicillin from culture of Penicillium notatum to Fleming in view of small stability of this A. V of 1940 (H. W. Florey, E. V. of Chain) developed a method of extraction of penicillin from cultural Penicillium notatum liquid, and high therapeutic activity of this drug was soon revealed.
Valuable properties of penicillin were an incitement to development of the industry of A. V of the USSR the first penicillin 3 were received. V. Ermolyeva in 1942. After discovery of penicillin intensive searches new began And., which proceed and still.
Most of scientists means under And. not only the antibacterial substances formed by microorganisms but also the connections having antibacterial activity, allocated from animal fabrics and the higher plants (see. Phytoncidal drugs ). More than 2000 are described And. also the set of derivative natural compounds, however is received And., suitable for a medical use, there are some tens. The others And. were too toxic, low-active or deprived of chemotherapeutic properties.
Classification of antibiotics
there are three philosophy on the basis of which it is possible to classify A.: 1) on an action spectrum, i.e. on character biol, an object, in the relation to-rogo this And. it is active; 2) on chemical structure And.; 3) on the molecular mechanism of action And. on a cell.
Classification of antibiotics by an action spectrum
And. it is accepted to divide on antibacterial, antifungal and antineoplastic. For medical practice such division is convenient since points to possible scope of this drug. Actually such division has many essential shortcomings because even relatives among themselves And. can differ strongly from each other on an antibacterial range of action. Can be examples And. from group of penicillin: one suppress development only of gram-positive microbes, others - both gram-positive, and gram-negative microbes.
Antibacterial antibiotics oppress development of bacteria. Some of them, napr, Benzylium penicillin, Makrolida, Ristomycinum (Ristocetinum, Spontinum), novobiocin and others, are active generally only concerning gram-positive microbes, others as they, e.g., polymyxin, suppress development of hl. obr. gram-negative bacteria, the third, napr, tetracyclines, levomycetinum (chloramphenicol, Chloromycetinum), aminoglucosides (streptomycin, Monomycinum, Kanamycinum, Neomycinum and gentamycin), so-called. And. a broad spectrum of activity, detain growth both many gram-positive, and gram-negative bacteria.
Antifungal antibiotics have the specific oppressing effect on growth of fungi. Broad use in medical practice was found And. the nystatin and levorinum used for the treatment of candidiasis and other diseases caused by drozhzhepodobny mushrooms. The antibiotic Amphotericinum of B is applied to treatment of generalized and deep mycoses. These three drugs concern to group half-yen And. From antifungal And. not half-yen structure griseofulvin was very effective remedy.
Antineoplastic antibiotics. It is established that some And. oppress development not only bacteria and fungi, but are also capable to detain reproduction of cells of malignant tumors. Some of these drugs found application in medical practice.
Antineoplastic And. include six groups of chemical connections which representatives are used in clinic.
The first group is made by Actinomycinums opened in 1940. Because of high toxicity they did not draw attention to themselves for a long time. Only in 1952, in animal experiments with the intertwined tumors, it was established that Actinomycinums suppress development of many intertwined tumors. In clinic Actinomycinums are applied generally to treatment of an adenocarcinoma of a kidney of a pla of a tumor of Vilms at children.
Second group antineoplastic And. - these are antibiotics anthracyclines. The most important representative of this group - rubomitsin - is one of the main pharmaceuticals for treatment of a horionepitelioma of a uterus and acute leukoses. Rubomitsin at this serious illness quite often leads to clinical recovery.
Third group antineoplastic And. consists of derivatives of aureolovy acid. Belonging to this group A. Olivomycinum is applied generally to treatment of tumors of a small egg, including seminomas, teratoblastomas and embryonal crayfish in a stage of generalization with metastasises in lungs, abdominal organs and limf. nodes. Other important indication for use of Olivomycinum are the tonsillar, quickly metastasizing tumors of a nasopharynx.
Fourth group antineoplastic And. it is presented in the Soviet Union by an antibiotic Bruneomycinum. The main indication to use of Bruneomycinum in clinic is the lymphogranulomatosis.
The Japanese researchers implemented in medical practice two antineoplastic A. Pervy from them a polypeptide antibiotic Bleomycinum is applied to treatment of epithelial tumors. The second antibiotic mitomitsin With is the representative of new special group of antibiotics porphyry and is new.
Still among waste products of microorganisms the connections interfering replication of viruses in living cell were not revealed. American And. hundred-tala it and elenin, detaining development of some viral infections in animals, there were interferonogenam (see. Interferon ).
Classification of antibiotics by a chemical structure
Classification of antibiotics by a chemical structure is more rational. It allows to compare structure of Ampere-second the mechanism of their antimicrobic action, side effects and processes of removal from an organism. And. treat various groups of chemical connections. To group A. an acyclic structure antibiotics of a polnena, including nystatin, Amphotericinum of B, trichomycin, kanditsidin, etc. belong. Antibiotics of tetracycline structure - concern to other group see. Tetracyclines . The hygromycin applied in veterinary science as protivogelmintny means belongs to antibiotics of an aromatic structure. Belongs to group of oxygen-containing heterocyclic antibiotics antifungal And. the griseofulvin which is widely used in dermatology and also antibacterial And. novobiocin, active concerning gram-positive cocci. In separate group Makrolida's antibiotics having the macrocyclic lactonic ring connected with one or several carbohydrate remains in the molecule are allocated (see. Makrolida ). A row important in the medical relation concerns to this group And.: erythromycin, Oleandomycinum, etc. It is close to macroleads and antibacterial And. lincomycin. To anthracyclines treats antibiotics antineoplastic And. rubomitsin. The group of the aminoglikozidny antibiotics constructed of the remains of an aminocyclitis and carbohydrates includes streptomycin and its derivatives (see. Streptomycin ), Neomycinum, Kanamycinum, Monomycinum and gentamycin. In separate group the penicillin which is most widely applied in medical practice is carried (see. Penicillin ). Gramicidins, tyrothricins, bacitracin, polymyxins, lysozymes, Viomycinum (florimitsin), colicines, etc. belong to antibiotics to polypeptides or proteins. Treats the polypeptides containing iron And. Albomycinum. Quite homogeneous group antibiotics make Actinomycinums having antineoplastic activity (see. Actinomycinums ). At last, numerous antibiotics streptothricins which in view of high toxicity did not find application in medical practice are carried to the last group. Attempts to use some become And. from this group in agriculture.
Classification of antibiotics by the molecular mechanism of action
the Most important for medical practicians A. it is possible to subdivide into several groups: 1) striking synthesis of a bacterial cellular cover (Penicillin, Ristomycinum, Vancomycinum, novobiocin, D-Cycloserinum, etc.); 2) breaking protein synthesis in a bacterial cell (And. tetracycline structure, Makrolida, levomycetinum, etc.); 3) (aminoglycosides) suppressing protein synthesis in a bacterial cell and at the same time breaking reading of a genetic code in the course of broadcasting; 4) oppressing synthesis of nucleic acids in cells (Rifamycinums, antineoplastic And.); 5) breaking integrity of a cytoplasmic membrane in cells of fungi (antifungal And. Polyenes).
After clarification of chemical structure of the majority And. attempts to carry out chemical synthesis by A. Uspeshny were made there was a synthesis of levomycetinum, and in a crust, time he is trained in exclusively chemical way. Though synthesis of some other And. it was possible (penicillin, gramicidin, etc.), but practically receiving them by means of microorganisms producers is simpler and economically more favorable, than receiving by their way of chemical synthesis.
In the beginning And. were applied in that look in what they were synthesized by microorganisms. However in process of development of chemistry And. methods of improvement of properties natural were developed And. by partial change of their chemical structure. Were received by such way so-called semi-synthetic And., in which the main kernel of an initial molecule native remains And., but some radicals of a molecule are replaced with others or removed. Especially great success was achieved in receiving semi-synthetic penicillin (see. Penicillin , semi-synthetic). It is shown what a kernel of a molecule of penicillin is 6-aminopenicillanic to - that (6-APK), having weak antibacterial activity. At accession to a molecule 6-APK of benzilny group receive benzylpenicillin which in a crust. time is developed at the plants of the medical industry and penicillin is widely applied in medical practice under the name. Benzylpenicillin has much higher antibacterial activity, than 6-APK. However benzylpenicillin along with very powerful chemotherapeutic activity and small toxicity possesses also nek-ry shortcomings: it is active generally only concerning gram-positive microbes, easily collapses under the influence of enzyme of the penicillinase formed by nek-ry microorganisms which thanks to it are steady against its action. Especially often among pathogenic bacteriums producers of a penicillinase are staphylococcus. The majority of the stafilokokk steady against penicillin allocated in clinic forms a penicillinase. Besides, Benzylium-penicillin quickly loses the activity in acid and alkaline environments and thanks to it collapses in went. - kish. path. From a molecule of benzylpenicillin it is possible to separate the benzilny rest and to replace it with the rest of a molecule of other organic compound.
Thus hundreds of various semi-synthetic penicillin were received (derivatives 6-APK). Most of them is of smaller interest, than initial benzylpenicillin. But some of the received semi-synthetic penicillin were steady against action of a penicillinase, e.g. Methicillinum which is effective also at treatment of the infections caused steady against benzylpenicillin of a stafilokokkama. Other semi-synthetic Penicillin steady against a penicillinase were resistant at acid reaction of the environment (Oxacillinum). Drugs of this type can be appointed inside. There is semi-synthetic Penicillin with much wider range of antibacterial action, than initial Benzylium-penicillin which detain growth of many gram-negative microbes (ampicillin).
Among tetracycline And. the derivatives which are allocated from an organism much more slowly and therefore their medical dosages are 5 - 10 times less, than dosages of initial natural tetracyclines were received. From And. Rifomycinum of SV it was received derivative rifampicin - effective antitubercular drug which besides is much more active concerning gram-negative bacteria, than initial Rifomycinum of SV. New semi-synthetic derivatives of lincomycin, levomycetinum etc.
the Mechanism of action of antibiotics
On the nature of action were received And. on a bacterium they can be divided into two groups: And. bacteriostatic actions and And. bactericidal action. Bacteriostatically And. in concentration which can be created in an organism detain growth of microbes, but do not kill them whereas influence bactericidal And. in similar concentration leads of cells to death. However in higher concentration bacteriostatically And. can render as well bactericidal action. To bacteriostatic And. tetracyclines, levomycetinum, etc., and belong to bactericidal - Penicillin, cephalosporins, Ristocetinum, aminoglycosides, etc. Makrolida.
In recent years great success was achieved in studying of the mechanism of action And. at molecular level. Penicillin, Ristomycinum (Ristocetinum), Vancomycinum, novobiocin, D-Cycloserinum break synthesis of a cell wall of bacteria, i.e. these And. affect only the developing bacteria and are almost inactive concerning the based microbes. Net result of action of these And. oppression of synthesis of murein which along with teykhoyevy acids is one of the main polymeric components of a cell wall of a bacterial cell is. Under the influence of these And. again formed cells deprived of a cell wall collapse. If to increase the osmotic pressure of surrounding liquid, e.g., do not lyse with entering into the environment of sucrose, then the bacteria deprived of cell walls, and turn into spheroplasts or protoplasts (see. Protoplasts bacterial ), who in the corresponding conditions are capable to breed like L-forms bacteria (see). After removal And. the microbic cell if she did not die, becomes again capable to form a cell wall and turns into a normal bacterial cell. Between these And. there is no cross stability because points of application them in the course of biosynthesis of murein are various. Since all above-mentioned And. strike only the sharing cells, bacteriostatic And. (tetracyclines, levomycetinum), stopping cell fission, reduce activity bactericidal And., and therefore their combined use is not justified.
Mechanism of action of others antibacterial And. - levomycetinum, macroleads, tetracyclines - consists in disturbance of synthesis of protein of a bacterial cell at the level of ribosomes. As well as And., suppressing formation of murein, And., oppressing synthesis of protein, operate on various stages of this process and therefore have no cross stability among themselves.
Mechanism of action And. aminoglycosides, napr, streptomycin, consists first of all in suppression of synthesis of protein in a microbic cell due to impact on 30 S-ri-bosomalnuyu subunit (see. Ribosomes ), and also disturbances of reading of a genetic code in process broadcastings (see).
Antifungal And. polyenes break integrity of a cytoplasmic membrane at a fungal cell therefore this membrane loses properties of the barrier between contents of a cell and external environment providing selective permeability. Unlike penicillin, polyenes are active also concerning the based cells of fungi. Antifungal action half-yen And. it is caused by their linkng with the sterols which are contained in a cytoplasmic membrane of cells of fungi. Stability of bacteria to half-yen And. is explained by absence in their cytoplasmic membrane of the sterols contacting polyenes.
Antineoplastic And., unlike antibacterial, break synthesis of nucleic acids in bacterial and zooblasts. And. Actinomycinums and derivatives aureolovy to - you suppress synthesis of RNA DNA-dependent, contacting DNA serving as a matrix for synthesis of RNA. And. mitamitsin With has the alkylating effect on DNA, forming strong covalent cross bonds between two complementary spirals of DNA, breaking at the same time it replication (see). And. Bruneomycinum leads to sharp oppression of synthesis of DNA and its destruction. Has overwhelming effect on synthesis of DNA and rubomitsin. All these reactions are probably primary and the main in operation And. on a cell since they are observed already at very weak concentration of drugs. And. in big concentration break many other biochemical processes proceeding in a cell, but, apparently, this influence And. is of secondary importance in the mechanism of their action.
the Producer is grown up in 10-50-ton reactors in conditions, optimum for education And. For the best aeration Wednesday constantly mixes up and through it pass sterile air since a mold and radiant fungi, the main producers of antibiotic substances, are aerobes (see). Successful production And. it is based on deep studying of physiology of producers: definition of optimum sources of nitrogen and carbon for education And. is necessary. One of the most important conditions of successful production And. productivity of a strain of a producer is. The strains of producers allocated from the environment usually from the soil, as a rule, are unproductive. By their selection it is possible to receive strains of producers in tens and hundreds of times more productive, than a stock «wild» strain. Duration of cultivation of a producer fluctuates of 48 hours to several days. Majority And., being of interest to medicine, collects in cultural liquid. Upon termination of cultivation of a producer cultural liquid is separated from a mycelium filtering and And., contained in liquid, allocate with various methods depending on its nature.
There are two main methods of allocation And. The first method consists in extraction And. from cultural liquid organic solvents, the second - is based on ability And. to be adsorbed on ion-exchange resins. For purification of drug use, depending on the nature And., various physical. - chemical methods.
The purified drugs A. for parenteral use usually release in the form of sterilely the dry powder packaged in bottles, well water soluble, isotonic solution of sodium chloride or solutions of novocaine. In recent years resistant And. are issued in the form of ready for application sterile solutions in bottles. For intake And. release in the form of tablets or in gelatin capsules. Many And. (tetracyclines, Neomycinum, erythromycin, gramicidin C, Geliomycinum, etc.) are used for preparation of ointments. For children's practice there are special dosage forms: the suspension of tetracycline, stearate of levomycetinum deprived of bitter taste, etc.
Check on biological activity of the majority And. it is carried out by microbiological methods (see. Antagonism of microbes ). For many And. as test-microbes soil bacilli (Bacillus subtilis, Bacillus mycoides), etc. are used. Activity of penicillin is defined concerning golden staphylococcus (a strain 209).
For definition of activity, some And. also chemical methods are applied. For penicillin the yodometrichesky method, for definition of activity of griseofulvin - a spectrophotometric method is used.
Take the specific activity which is contained in 1 mkg of pure drug A for the international activity unit (PIECE) of the majority of antibiotics. For penicillin the international unit (PIECE) of activity equals 0,6 mkg. This quantity corresponds to the minimum quantity of penicillin detaining growth of a standard strain of staphylococcus in 50 ml of a medium. For an activity unit And., which still are finally not cleared, accept the minimum quantity of the purest drug detaining growth of a test-microbe in 1 ml of a medium. Concentration of dry drugs A. it is expressed in number of units of active agent in 1 mg of drug.
Use of antibiotics
And. are very widely applied in medical practice to treatment of various bacterial, fungal infections and some tumors. Rational use And. is based on exact knowledge of their pharmacological and chemotherapeutic properties.
Progress of an antimicrobic antibioticotherapia first of all depends on sensitivity of an infestant to the used drug, forms of pathological process, a phase of a disease and a condition of protective mechanisms of an organism. At appointment antimicrobic And. it is necessary, considering sensitivity of the activator to And., to appoint whenever possible the most active of them. At hron, diseases it is reasonable to define sensitivity of the activator to And. in vitro every 10-15 days treatment. In case of a serious illness when treatment needs to be begun perhaps quicker, usually appoint And. broad spectrum of activity. Final treatment is appointed after definition of sensitivity of the activator to And.
Doses And. it is necessary to appoint to reach antibacterial concentration in the centers of defeat. Majority And. it is quickly allocated and therefore for maintenance of efficiency concentration of drug in an organism And. usually enter to the patient several times in days, depending on the speed of their allocation.
Indications and dosages And. - see in articles according to the name of separate drugs.
Success of treatment is harmed by emergence of stable forms of microbes. For the prevention of emergence of stable forms of activators simultaneous use of two or bigger numbers of antibacterial drugs with various mechanisms of action since stability at the activator develops much more slowly to two Ampere-second various mechanisms of action, than to one drug is recommended. Well proved the following combinations in clinic And.: tetracycline with And. macroleads - Oleandomycinum (Oletetrinum) or erythromycin, penicillin with streptomycin (at treatment of acute infections, but not tuberculosis). Combine Ampere-second with success synthetic chemotherapeutic drugs, napr, for treatment of tuberculosis streptomycin usually appoint along with an isoniazid (hydrazide isonicotinic to - you) and p-aminosalicylic to - that (PASK). At acute diseases often appoint And. and sulfanamide drugs. It is not recommended to appoint at the same time And., the sharing cells (penicillin) operating on and bacteriostatic And. (tetracyclines) since under the influence of the last cell fission stops and penicillin loses the activity.
Antineoplastic And. are appointed in clinics only according to strictly established indications for each drug.
And. are not substances, indifferent for an organism, and, having high therapeutic activity, are capable to cause a number of more or less heavy side reactions. Recovering, receiving during a disease And., have less hyperimmunity, than recovering, not receiving And. A recurrence of a disease is celebrated more often at recovering from a typhoid, receiving levomycetinum during the acute period of a disease, than at recovering, not receiving it And. Therefore sometimes an antibioticotherapia is combined with vaccinotherapy, especially at a typhoid. Antineoplastic And. in itself strongly oppress an immunogenesis.
Quite often And. cause various complications of the allergic nature, limited and generalized damages of skin (see. Toxidermias ), Quincke's edema, vasculomotor rhinitises and arthralgias. Usually the first predecessor of allergic reactions is the eosinophilia. Immediately after introduction And. it can be observed acute anaphylaxis (see), especially after administration of penicillin and is much more rare after administration of streptomycin. Therefore at use of penicillin, especially at the patients receiving it earlier it is necessary to put skin sensitivity tests to penicillin. Though skin tests also not always allow to reveal hypersensitivity to penicillin, nevertheless they allow to avoid at a part of patients of heavy allergic reactions.
One of the most often observed complications at use And. superinfections or consecutive infections are. Use And. leads to disappearance from an organism of saprophytic microorganisms, sensitive to them. Instead of them in an organism begin to breed steady to And. conditionally pathogenic bacteriums and fungi: colibacillus, proteas, staphylococcus, yeast-like fungi etc. which in certain conditions can cause development of more or less heavy consecutive infection. Steady staphylococcus, developing after reception of tetracyclines, sometimes cause heavy coloenterites, yeast-like fungi lead more often to development of local defeats (on mucous membranes), is more rare - generalized diseases (see. Candidiasis ).
Destruction under influence And. normal intestinal microflora leads sometimes to avitaminosis since colibacilli are producers of vitamins of group B and partly groups K. Therefore at prolonged use And. it is recommended along with And. to appoint polyvitamins and in particular vitamins of group B.
And. can have also direct toxic effect on an organism; e.g., aminoglycosides selectively affect the VIII pair of cranial nerves and cause vestibular frustration or irreversible deafness; some of them cause more often vestibular frustration (streptomycin, gentamycin) whereas others (Neomycinum, Monomycinum, Kanamycinum, de hydrostreptomycin) at the wrong appointment lead to irreversible deafness. Special danger is constituted in this respect by Neomycinum which therefore it is not necessary to apply parenterally. It is also impossible to appoint at the same time two And. aminoglycoside or to apply one aminoglycoside immediately after the termination of introduction of other representative of this group. A. Macroleads and tetracyclines in high doses can cause damage of a liver, and levomycetinum, though is very rare, strikes a hemopoiesis and leads to an irreversible aplasia of marrow. Antineoplastic And. cause many side reactions, the heaviest of them are connected with disturbances from outside went. - kish. path and oppression of a hemopoiesis.
Considering a possibility of the heavy side reactions caused And., their use shall be carried out always under careful observation of doctors.
It is necessary to fight against self-treatment of patients, a cut often does more harm, than advantage.
Resistance of bacteria to antibiotics
Widespread introduction And. in applied medicine and veterinary science led to distribution of the bacteria steady against action And. Such bacteria can be divided into two groups: 1) steady against one And. and 2) steady at the same time to several And. (multiple resistance). Bacteria of the first group can be steady and to several And., if the last are characterized by a close chemical structure and the unambiguous mechanism of action on a bacterial cell (cross stability). E.g., the bacteria steady against action of Rifamycinum are at the same time steady against a streptovaritsin at the expense of the mechanism of the action, uniform for these drugs, connected with dysfunction of a RNA polymerase. Resistance to streptomycin is combined with dihydrostreptomycin resistance and, partially, to Neomycinum, i.e. subject to action for all these And. proteins in 30 S-subjedinine of a ribosome are.
Genetic control of level of sensitivity to And. is defined by the genes localized in bacterial chromosomes or in transmissibelny plasmids (see). The last provide multiple resistance of a cell to several And. (see. R-factor ).
A bacterium, resistant to this And., represents a mutant on the corresponding chromosomal gene which controls structure of the components of a cell which are subject to action And. The mutations on chromosomal genes leading to an antibiotikorezistentnost arise with a low frequency, fluctuating from 10 - 6 to 10 - 12 . Therefore emergence of at the same time chromosome mutations to two or more And. it is almost impossible. The bacteria bearing chromosome mutations to two or more And., result from an independent mutation in a strain, initially resistant to one of And.
The molecular mechanism which is the cornerstone of resistance of a mutant bacterium for different And. it is various and is defined by damage of the structures of a cell interacting with this And. Gorini's researches, Katayi, Trauba and Nomura (L. Gorini, E. Kataja, 1964; P. Traub, M. of Nomura, 1968) showed that streptomycin inactivates the 30th S-subunit of a ribosome due to interaction with the 10th protein entering into its structure therefore broadcast of genetic information is broken and synthesis of a polypeptide chain is distorted. The mutation on a gene of str A leads to structural change of the 10th protein therefore the last loses ability to interact with And. From Hayl's works and Tsilliga (A. Heil, W. Zillig, 1970) other example of an antibiotikorezistentnost which is also connected with mutational change of the cellular substrate which is subject to action of A. Bakteriya, resistant to Rifamycinum is known - And., inactivating a RNA polymerase, contain enzyme, insensitive to it And. at the expense of izmelenny subunit of enzyme therefore the complex of a molecule of a RNA polymerase with Rifamycinum is not formed. Other mechanism providing resistance of bacteria to And., disturbance of process of its penetration into a cell and accumulation in it is. Gram-negative bacteria of a rezistentna to action of Actinomycinum because of its inability to get through a cell wall. Processing of these bacteria ethylene diamine tetraacetic to - that (EDTA) increases their sensitivity to A. Poluchena the bacterial mutants steady against EDTA and at the same time become resistant to Actinomycinum. Reeve and Bishop's researches (C. Reewe, E. Bishop, 1965) showed, that the resistance of bacteria to chloramphenicol (levomycetinum) which resulted from mutations in a chromosome is also connected with disturbance of permeability of a bacterial membrane for this And.
In the world of bacteria the enzymatic mechanism of resistance is eurysynusic to And. It consists in transformation active And. in an inactive form as a result of action on it the modifying enzymes of a cell. This type of resistance is controlled by hl. obr. The R-plasmids bearing various combinations of genes of resistance to the following And.: to ampicillin, chloramphenicol, Kanamycinum, streptomycin, spektinomitsin, gentamycin and tetracycline. Possibly, the resistance of bacteria controlled by plasmids is not limited listed And., which list constantly increases γιο to a measure of opening of new R-factors and creations of new drugs A. The resistance determined by R-plasmids is widespread among the bacteria relating to different childbirth and families: Shigella, Escherichia, Salmonella, Proleus, Pseudomonas, Staphylococcus. The molecular mechanisms providing stability of the bacteria bearing a R-factor (R + - cells), to different And., are various. Penicillin resistance is connected with synthesis of a penicillinase (ß-laktamazy), controlled one of genes of a R-factor. This enzyme hydrolyzes ß-laktamnoye a ring of penicillin. Sava (T. Sawai, 1970) and coauthors established that there are three types of the penicillinases differing from each other on physical. - to chemical, enzymatic and immunological properties. Along with plazmidospetsifichny penicillinases penicillinases which synthesis is controlled by chromosomal genes are found in bacteria. They are capable to inactivate all known derivatives of penicillin and cephalosporin.
Resistance of R + - bacteria to chloramphenicol is defined by effect of enzyme of the hloramfenikolatsetiltransferaza coded by a gene of a R-factor. As a result chloramphenicol turns in inactive O-atsetilderivat. Resistance to And. an aminoglycosidic group in R + - bacteria is defined by presence at a cell of five enzymes modifying And. in an inactive form: streptomitsinfosfotransferaza, streptomitsinadenilatsintetaza, kanamitsinatsegiltransferaza, kanamitsinfosfotransferaza, gentamitsinadenilatsintetaza, and the last enzyme inactivates also Kanamycinum and Tobramycinum.
The inactivation of streptomycin is carried out in R+ cell the first by two of the mentioned enzymes and consists in accession to 3-IT-group A. phosphate or AMF which donor is ATP. There is a direct correlation between resistance of R + - strains to Kanamycinum and Neomycinum and presence at them of the third and fourth of above-mentioned enzymes. The acetylating enzyme has a nek-swarm specificity concerning type of Neomycinum, napr, acetylation of Neomycinum In is not followed by its full inactivation.
Thus, inactivation And. in R + - the strains which are characterized by multiple resistance it is carried out by three types of reactions - phosphorylation, acetylation and an adenilirovaniye. Studying of biochemical mechanisms of stability of bacteria to And. showed that resistance to separate And. it is not always controlled by an individual gene of a R-factor. In other words, the bacterium can have resistance to bigger number A., than number of the genes controlling these signs. It is connected with the fact that individual enzyme, synthesis to-rogo is determined by one gene, is capable to inactivate different A. Nekotorye from the enzymes inactivating And., synthesized under control of a R-factor, are localized in a cell in periplazmatichesky space. The R-penicillinase, streptomitsinadenilatsintetaza and streptomitsinfosfotransferaza belongs to such enzymes. Hloramfenikolatsetiltransferaza is not found in periplazmatichesky space.
Interpretation of the biochemical and genetic mechanisms providing resistance of bacteria to And., proves rationality of their clinical use, ways of overcoming resistance of bacteria and an orientation of search of new medical drugs. Overcoming a multiple antibiotikorezistentnost of bacteria can be theoretically reached by use of the drugs which are selectively blocking replication of a R-factor (drugs of an acridic row) or by an inactivation of the enzymes modifying A. Odnim from possible approaches for fight against the antibiotikorezistentnost connected with effect of R-enzymes the combined use of drugs, one of which protect others from an inactivation, is. E.g., gentamycin is capable to oppress in low concentrations an inactivation of other aminoglycosides. From H. Umezawa's works it is known that a number of simple sugars, e.g. the 3-amino-3-dezoksi-d-glycosamine, suppresses phosphorylation of Kanamycinum the enzyme emitted from Pseudomonas.
Bibliography: Antibiotics, M., since 1956; Antibiotics, collections of translations, M., 1948-1959; Antibiotics, under the editorship of P. N. Kashkin and Η. P. Blinova, L. 1970, bibliogr.; Vaksman 3. A. Antagonizm of microbes and antibiotic substances, the lane with English, M., 1947; And the m is scarlet e I Η. T. Collected works, t. 2, page 336, M., 1951, bibliogr.; And at z e G. F. Lectures on antibiotics, M., 1958, bibliogr.; Grovd. Page irendallv. A. The guide to laboratory methods of a research of antibiotics, the lane with English, M., 1958, bibliogr.; Ermolyeva 3. B. Antibiotics, Interferon, Bacterial polysaccharides, M., 1968, bibliogr.; A clinical use of antibiotics, under the editorship of V. of X. Vasilenko, etc., M., 1966; Skin y bek of T., Kovshyk-Gindifer 3. and Kurylovich V. Antibiotics, an origin, the nature and properties, the lane with polsk., t. 1-2, Warsaw, 1969; Krasilnikov H.A. Antagonism of microbes and antibiotic substances, M., 1958, bibliogr.; The quick reference guide on an antibioticotherapia, under the editorship of I. G. Rufanov, M., 1964, bibliogr.; The mechanism of action of antibiotics, the lane with English, under the editorship of G. F. Gauz, M., 1969, bibliogr.; N and - in and sh both N S. M. and Fominai.P. Reference book on antibiotics, M., 1974, bibliogr.; Planelyes X. and Kharitonova A. By-effects at an antibioticotherapia of bacterial infections, M., 1965, bibliogr.; Antineoplastic antibiotics, under the editorship of M. M. Mayevsky, M., 1962, bibliogr.; Saza Kean Yu. O. Antibiotics as inhibitors of biochemical processes, M., 1968, bibliogr.; B. P token. Phytoncides, Sketches about antiseptic agents of a plant origin, M., 1948; Shemyakin M. M., etc. Chemistry of antibiotics, t. 1-2, M., 1961, bibliogr.; Sh about r and V. A N. The complications caused by antibiotics, M., 1958; W e 1 with h H. Principles and practice of antibiotic therapy, N. Y., 1954.
Resistance of bacteria to A. Kudlay D. G., Chubukov V. F. and Oganesyan of M. G. Genetik of medicinal stability of bacteria, M., 1972; Davies J. E. Rownd R. Transmissible multiple drug resistance in entero-bacteriaceae, Science, v. 176, p. 758, 1972; Goldberg I. H. a. Friedman P. A. Antibiotics and nucleic acids, Ann. Rev. Biochem., v. 40, p. 775, 1971; G o-rini L. Kataja E. Phenotypic repair by streptomycin of defective genotypes in E. coli, Proc. nat. Acad. Sei. (Wash.), v. 51, p. 487, 1964; Heil A. Z i 1 1 i g W. Reconstitution of bacterial DNA - dependent RNA - polymerase from isolated subunits as a tool for the elucidation of the role of the subunits in transcription, FEBS letters, v. 11, p. 165, 1970; Traub P. Nomura M. Structure and function of E. coli ribosomes, Proc. nat. Acad. Sei. (Wash.), v. 59, p. 777, 1968.
V. A. Shornn; D. M. Goldfarb (Stability of bacteria). Authors of tables A. M. Marshak, I. V. Martynov.
TABLES (the annex to the article «Antibiotics»)
Basic purpose of the tables given below - to promote more rational medical use of antibiotics. Materials of tables are indicative and therefore in specific clinical circumstances the known deviations from tabular recommendations are admissible. Tables included those types of causative agents of infectious diseases and pyoinflammatory processes which sensitivity to the majority of antibiotics is studied adequately. In the absence of the relevant data in table 3 crossed out sections are made. The drugs produced or which are widely applied in the USSR are included in the list of antibiotics generally (data for 1975).
Table 1 characterizes sensitivity of in vitro of separate types of causative agents of infectious diseases to various antibiotics. On the basis of materials of the table it is possible to allocate a number of antibiotics, use of each of which against this type of the activator is represented theoretically justified.
Table 2 contains recommendations of priority of use of antibiotics in treatment of bacterial pyoinflammatory processes. In the absence of clinical and bacteriological data on sensitivity (resistance) of the activator the antibiotic of the first stage can be recommended for antibiotics. At weak effect or its absence one of reserve drugs can be applied.
Table 3 allows to establish (approximately) optimum dose of concentration of drug suppressing growth of this agent of infection.
The single doses and ways of introduction of antibiotics providing the effective level of their concentration in blood are presented in table 4.
Thus, having made the choice of an antibiotic (with use of data from tables 1 and 2) and having planned - by means of tables 3 and 4, and also taking into account specific clinical data - the size of a single dose of an antibiotic, optimum for the patient, check according to table 5. whether this size exceeds limits, admissible for this antibiotic. The approximate frequency rates of daily administration of drug and duration of its use given in the same table help to choose an effective course of treatment.
More detailed information about features of use of various antibiotics at treatment of the diseases caused by separate activators is given in the relevant articles.
Table 1. Sensitivity of some microorganisms to antibiotics
Symbols: +++ are highly sensitive; ++ are sensitive; + are insensitive; ± are sensitive changeably; - are steady.
- - Some strains are sensitive to high concentration of drug.
Table 2. Priority of use of antibiotics at the purulent and inflammatory processes caused by bacteria
Table 3. Range of the minimum concentration of antibiotics (in vitro), overwhelming causative agents of infections
Table 4. Definition of a dose and way of introduction of the antibiotic providing the necessary level of its concentration in blood serum
Symbols: + this concentration of an antibiotic in blood is provided.
- &1nbsp; The Time interval is chosen taking into account widespread schemes of introduction of antibiotics.
- &2nbsp; For convenience of orientation all drugs are grouped on the basis of uniformity of action (bactericidal or bacteriostatic), uniformity of distribution in an organism and uniformity of toxicity. It is important to consider it at the combined antibacterial therapy: the best effect renders a combination of the same operating drugs, and a contraindication for a combination of antibiotics is their same toxicity.
- &3nbsp; It is not recommended to appoint at the same time two drugs of this group (an interval not less than 10 days).
- &4nbsp; At increase in a dose to &300nbsp; &mgnbsp; concentration increases to &7nbsp; mkg/ml.
Table 5. Approximate range of single doses, frequency of introduction and duration of use of antibiotics with the medical purpose depending on a way of introduction
- For children till 1 year of 3 — 5 times. * &2nbsp; For children 3 — 4 times.
ANTIBIOTICS — the chemotherapeutic substances formed by microorganisms or received from fabrics of plants and animals and also their synthetic analogs and derivatives having ability selectively to suppress in an organism of the patient viability of causative agents of diseases (bacteria, fungi, viruses, the elementary) or to detain development of malignant new growths.
Vast majority And., having practical value, receive in a commercial scale by biosynthesis them actinomycetes, the lowest fungi (penicillia, tsefalosporiuma, etc.) or nek-ry bacteria. More than 2000 are described And., at 200 of them the mechanism of action is studied, use in medicine was found apprx. 50 A., to answering criteria of efficiency and harmlessness. And. apply also in veterinary science, to stimulation of growth of page - x. animals and birds, in the food industry. And. belong to the most various classes of chemical connections (aminosugar, anthraquinones, quinones, glycosides, lactones, Makrolida, phenazines, piperazins, pyridines, quinones, terpenoids, tetracyclines, triazines, etc.). Beta lactamides (Penicillin and cephalosporins), Makrolida (erythromycin, Oleandomycinum, etc.), ansamakrolid (Rifamycinums), aminoglycosides (streptomycin, Kanamycinum, gentamycin, Tobramycinum, sisomicin, etc.), tetracyclines, polypeptides (bacitracin, polymyxins, etc.), polyenes (nystatin, Amphotericinum In, etc.), steroids (Fusidinum), anthracyclines are most widely applied (daunorubitsin, etc.).
Molecules natural And. in that look in what they are produced at biosynthesis, are not ideal for medical practice on chemotherapeutic and pharmakol, to indicators. Broad development directed chemical and mikrobiol, transformations And. led to creation so-called semi-synthetic And., having new properties, valuable to medicine: the l from - and en-zimo stability, the expanded range of antimicrobic action improved by the distribution in fabrics and liquids of an organism changed by the mechanism of action to microbic and tumor cells, smaller number of side effects turned sour. The best results are achieved during the receiving and use of semi-synthetic penicillin (see), cephalosporins (see), aminoglycosides, tetracyclines (see), Rifamycinums (see) which are the main representatives of the so-called antibiotics of second generation which succeeded traditional natural A. Nekotorye natural And., especially benzylpenicillin, hl are used. obr. for receiving semi-synthetic derivatives. Separate And. are applied only in the form of products of chemical transformation (cephalosporins, Rifamycinums, etc.).
Classification of antibiotics and their use
On an orientation (range) of action distinguish the following And.:
1) active concerning gram-positive microorganisms, especially stafilokokk: benzylpenicillin, semi-synthetic Penicillin and cephalosporins, Makrolida, Fusidinum, lincomycin;
2) a broad spectrum of activity (active concerning gram-positive and gram-negative microorganisms): tetracyclines, chloramphenicol (levomycetinum), aminoglycosides, semi-synthetic Penicillin and cephalosporins;
3) antitubercular And.: streptomycin, Kanamycinum, biomycin (florimitsin), Cycloserinum, etc.;
4) antifungal And.: nystatin, levorinum, Amphotericinum of B, griseofulvin, etc.;
5) active concerning protozoa: fumagillin, trichomycin, paromomitsin (Monomycinum);
6) antineoplastic And.: Actinomycinums, group aureolovy to - you, anthracyclines.
Though for a row A. in an experiment the possibility of antiviral action was proved (distamicinum And., derivatives of Rifamycinum, etc.), they did not find application for treatment of diseases of a virus etiology so far. Some And. possess anthelmintic action and are applied to treatment of helminthic invasions at page - x. animals, napr, hygromycin B.
Antimicrobic And. are applied in livestock production and poultry farming as growth-promoting factors, and also in the food industry at conservation of products. However use for this purpose A., widely used in medicine, can lead to serious effects, first of all distribution of activators with multiple resistance to And. the extra chromosomal (plasmid) nature which can be the reason of serious illnesses of the person, and also allergizations due to residual quantities And. in foodstuff. The legislation of a number of the countries forbade or limited use And., used in medicine, in livestock production and the food industry.
Some And. are widely used at biochemical, and molecular biol. researches as specific inhibitors of certain metabolic processes of cells micro and macroorganisms.
On the molecular mechanism of action And. carry to the following groups:
1) inhibitors of synthesis of a cell wall of microorganisms: Penicillin, cephalosporins, Cycloserinum, Vancomycinum, bacitracin;
2) inhibitors of function of membranes and And., having detergentny property: polymyxins, novobiocin, polyenes (nystatin, Amphotericinum of B);
3) inhibitors of synthesis of protein and function of ribosomes: tetracyclines, chloramphenicol (levomycetinum), aminoglycosides, Makrolida, lincomycin;
4) inhibitors of metabolism nucleinic to - t: a) RNA inhibitors — Actinomycinums, And. groups aurelovy to - you, anthracyclines, novobiocin; b) DNA inhibitors — mitomitsin With, Streptonigrinum (Bruneomycinum), novobiocin, lincomycin.
Knowledge of the mechanism of action And. at the cellular and molecular levels allows to judge not only an orientation of chemotherapeutic effect («target» And.), but also about degree of its specificity. So, e.g., beta lactamides (Penicillin and cephalosporins) influence basic polymer (peptidoglikan) of a cell wall of bacteria, absent at animals and the person. Therefore selectivity of action beta laktamidov is their unique property defining a high chemotherapeutic index and low level of toxicity that allows to enter these And. in high doses without danger of development of side effects. Selectivity of action And. — inhibitors of proteinaceous synthesis it is not so expressed. Therefore at use And. groups of tetracyclines, aminoglycosides and chloramphenicol (levomycetinum) in big percent of cases come to light side effects. At comparative analysis of properties of various groups A. they are estimated on efficiency factors and harmlessness, determined by expressiveness of antimicrobic action in an organism, the speed of development of stability in microorganisms in the course of treatment, lack of cross stability with other himiopreparata, extent of penetration into the centers of defeat, creation of therapeutic concentration in fabrics and liquids of the patient and lasting their maintenance, preservation of action in various conditions of the environment. Important properties are also shelf stability, convenience of use at different methods of introduction, the expressed gap between medical and toxic doses (a high chemotherapeutic index), absence or weak expressiveness of organotropic (toxic) by-effects, and also allergizations of the patient. Such criteria as etiotropnost And., established on the basis of tests concerning the allocated activators (studying of sensitivity for receiving a so-called antibiogramma), and a possibility of achievement of therapeutic concentration in an organism define effect of action And. at this disease.
Choice And. the wedge, and a lab is carried out on the basis of a complex. tests. At a close antibacterial range the least toxic is appointed And., more rare causing side reactions. Dose And., the way and frequency of its introduction are defined on the basis of comparison of MT To (the minimum concentration suppressing growth of a microorganism And.) for the allocated activator and the concentration reached in an organism at optimum doses and ways of introduction. Consider expedient that concentration And. in blood exceeded value of its MPK for this activator. At heavy septic processes, weakening of defense reactions of the patient it is necessary to appoint bactericidal And.; e.g., natural and semi-synthetic Penicillin and cephalosporins * aminoglycosides, polymyxins, etc. At sufficient doses data And. give bystry therapeutic effect, the number of a recurrence decreases and the carriage of activators is warned (endocarditises, sepsis, pyelonephritises, osteomyelites, tuberculosis, etc.). Bactericidal And. it is possible to apply courses with certain breaks. Bacteriostatic And. use usually at moderately severe diseases of a current. At the same time protective mechanisms of the patient complete chemotherapeutic action And. also exempt an organism from activators.
An indispensable condition for an etiotropic antibioticotherapia is bacterial, diagnosis of a disease, allocation of the activator and definition of its sensitivity to And.
For the contingents of the patients who are affected And., dominance of the senior age groups or, on the contrary, children of early age at whom conditions of distribution are sharply changed is characteristic And. in an organism. Often inf. process is followed by other diseases (cardiovascular, diseases of kidneys, a liver etc.) influencing effect of an antibioticotherapia. It must be kept in mind also the impact exerted by other medicines (especially corticosteroids, diuretics, immunodepressants), and also by such methods of treatment as radiation therapy, tool interventions etc.
the Problem of resistance of microorganisms to antibiotics
the Major factor reducing a net result of an antibioticotherapia is resistance (resistance) of microorganisms to A. Ustoychivost of microorganisms to And. it is studied from positions of genetics, molecular biology, ecology and epidemiology. Stability can be defined by natural properties of this look or sort of microorganisms, chromosome primary or secondary mutation (slow development of stability — a multistage mutation, bystry — a one-stage mutation). Multiple resistance at the same time to a row A. (polyresistance) is controlled by so-called R-factors (plasmids) localized in cytoplasm of a bacterial cell (extra chromosomal stability). Such form is described for the majority of bacteria — escherichias, shigellas, salmonellas, stafilokokk, etc. R-factors (see), the extra chromosomal DNA-containing elements have determinants of resistance to many And. and the genes responsible for transfer of information from a cell in a cell. Transfer of determinants of resistance from one cell to another can carry inside - or interspecific character. Transfer of resistance is carried out by means of 3 genetic mechanisms: transformations (see), transductions (see) and conjugation (see. Conjugation at bacteria ). The final journey is the most frequent and has major importance for epid, distribution of multiple stable forms of pathogenic bacteriums (a shigella, a salmonella, colibacilli, cholera vibrioes etc.). Along with determinants of resistance extra chromosomal elements can carry out transfer of other signs defining the activator (formation of toxins, hemolitic ability, etc.). Thus the strains of opportunistic microorganisms containing extra chromosomal factors of resistance get the additional selective advantages causing them epid, distribution.
Stability of microorganisms to And. is implemented through various biochemical, mechanisms. The main thing is the euzymatic inactivation (e.g., penicillin — beta lactamelements of resistant strains); change of permeability of a cell wall or blocking of transport matters And. (tetracyclines), disturbance of metabolism of a cell, change of intracellular acceptors — ribosomes, enzymes, etc. (aminoglycosides, Makrolida).
Knowledge of mechanisms of stability allows to create directionally derivative Ampere-second the modified properties, napr, protected from an euzymatic inactivation.
Comparative frequency of allocation of steady stafilokokk to benzylpenicillin makes 60 — 80%, to tetracycline and streptomycin — 50 — 70%, to chloramphenicol (levomycetinum) — 30 — 50%. The average figures characterizing stability of the most important activators — gram-negative bacteria (colibacilli, proteas, klebsiyella) to it And. a broad spectrum of activity as tetracyclines, levomycetinum and streptomycin, make 40 — 95%. The wide spread occurance of stable forms of microorganisms leads to the corresponding decrease in efficiency traditionally applied And., so-called. And. firstgeneration. Value of definition of sensitivity of the activator increases in these conditions to And., what is obligatory at a serious illness (sepsis, a septic endocarditis, bacterial meningitis, osteomyelitis, etc.), and also in all cases of intrahospital infections, etiol which factor most often are polyresistant microorganisms; at hron, infections of kidneys and urinary tract; at use And. against the background of use of corticosteroids and immunodepressants. In rare instances when the diagnosis of a disease can be made on the basis of revealed a wedge, symptoms or microscopy of smears from patol, material, use is possible And., active concerning estimated activators (streptococcal quinsy, a .skarlatina, pneumococcal pneumonia, an erysipelatous inflammation, gonorrhea, etc.). Depending on the frequency of detection of resistant forms all pathogenic microorganisms it is possible to divide into two groups conditionally: 1) not demanding definitions anti-biogrammy, since their sensitivity to And. significantly did not decrease (streptococci of group A., pneumococci, meningokokk, gonokokk, salmonellas, brucellas); 2) activators for which definition of sensitivity is obligatory since among them resistant strains often are found (staphylococcus of colibacillus, enterokokk, proteas, a pyocyanic stick, mycobacteria, etc.). Fight against distribution of stable forms of microorganisms at the patients who are on hospitalization (intrahospital, nozokomialny infections, a hospitalism) is a serious problem for clinical physicians, hygienists, microbiologists and epidemiologists. Most often these activators have the polyresistance caused by extra chromosomal elements (staphylococcus, gram-negative bacteria). Distribution of such strains in hospitals (especially in surgical and the Urals, departments, maternity homes) is connected with their selection selection under the influence of use And. and planting of the environment (patients, personnel, objects of leaving, tools etc.). In these cases use new is necessary And., effective concerning the allocated activator. However a decisive factor of fight with hospitalism (see) the most strict observance a dignity is. - a gigabyte. died, rules of an asepsis and antiseptics, identification of cases of a carriage of activators at personnel and its sanitation. Rational use And. in to lay down. institutions alternation of certain groups A provides constant control of dynamics of resistance of the main activators. and preservation in a reserve of the most effective drugs.
Stability of microorganisms to And. can have cross character both in certain groups, and between various groups A. It can be full (tetracyclines) or partial (aminoglycosides, Makrolida, etc.).
On degree of order to And. microorganisms carry to sensitive, moderately sensitive and steady. Sensitive consider those microorganisms which growth stops at the concentration reached in blood of patients during the use of average daily doses And.; moderately resistant strains are suppressed at purpose of the maximum doses of A. Rezistentnymi of activators consider when it is not possible to suppress their development in an organism during the use of the maximum doses And.
For definition of sensitivity of microorganisms to And. apply various methods: serial cultivations in a fluid or dense medium and diffusion in an agar; various methods which are also accelerated (express) are offered. Method of serial delution has quantitative character; during the use of fluid mediums receive more exact results, than in agarizo bathing environments. In view of labor input its use in daily a lab. to practice it is limited. The diffusion method in an agar with use of standard diagnostic disks is simplest and is widely applied with And., released by the industry according to the international requirements of WHO.
Before definition of sensitivity to And. material for crops (wound contents, exudates, blood, urine, etc.) is sowed on the selection environments (see). After allocation and identification of culture it is used for definition of sensitivity to And.
Definition of sensitivity of microbes to And. is a basis for the choice of optimum drug; In 80 — 85% of cases results of definition of sensitivity of activators correspond a wedge, to results of an antibioticotherapia. Discrepancy of results is connected with a variety of reasons from which leaders are the wrong interpretation of an antibiogramma, the wrong definition of a role in etiologies of a disease of the allocated microorganisms, and also feature of localization of activators (an intracellular arrangement, the hardly accessible centers of an infection).
Group of the parameters defining effect And., it is connected with conditions of ensuring optimum concentration And. in an organism: features of absorption, distribution in bodies, fabrics and liquids, removal, metabolic transformations. In particular, under certain conditions And. in an organism can communicate and be inactivated; to turn into inactive or toxic decomposition products. It is necessary to know conditions of penetration And. through hematoencephalic, placental barriers, in a bone tissue etc.
Comparison of the parameters characterizing kinetics of distribution And. in an organism, with values of the minimum overwhelming concentration of drug for the allocated activator gives the chance to calculate optimum doses and the modes of introduction And. Most often concentration And. in blood serum, urine, etc. define mikrobiol, methods (serial dilutions, diffusion in an agar). Use also physical. - chemical methods, however they are less effective owing to possible definition and inactive decomposition products A. At establishment of effect of use And. it is necessary to take into account degree and the nature of its linkng with serum proteins, and also incompatibility and a possibility of an inactivation And. other medicinal substances. At a size of concentration And. also extent of absorption of various dosage forms influences And. depending on physical. properties of substance (crystal form, solubility etc.).
See also Medicinal stability of microorganisms .
The characteristic of the major groups of antibiotics
Betalaktamny antibiotics (beta lactamides) combine two groups: Penicillin (see) and the cephalosporins (see) which are the leading and most effective remedies of a modern antibioticotherapia. These And. possess the following the general: properties: bactericidal type of action, high activity concerning first of all gram-positive bacteria, bystry approach of antibacterial effect and preferential influence on bacteria in a stage of proliferation; ability to get into a cell and to influence on the activators which are in it; slow development in microorganisms of stability in the course of treatment, a hypotoxicity for a macroorganism and good tolerance even at prolonged use of high doses.
Penicillin includes the following basic groups: 1) biosynthetic Penicillin (benzylpenicillin, its salts and ethers, phenoxymethylpenicillin); 2) semi-synthetic Penicillin: a) active it is preferential concerning gram-positive bacteria (Methicillinum, drugs of izoksazolilovy group — Oxacillinum, dikloksatsillin, kloksatsillin, flukloksatsillin, etc.), b) a broad spectrum of activity (ampicillin, amoxicillin, tikartsillin, tsiklotsillin, karbenitsillin).
Penicillin is specific inhibitors of synthesis of a cell wall of a bacterium, suppressing the last stage of synthesis of its basic polymer of the peptidoglikan occurring only during active growth of bacteria. Benzylpenicillin — widely implemented in 40 — is the 50th 20 century in medical practice the first A. Yavlyaetsya high-selective drug for treatment of the infections caused by stafilokokka sensitive to its action, streptococci, meningokokka, etc. (except for enterococci). The minimum overwhelming concentration for sensitive strains makes from 0,001 — 0,05 PIECES of j of ml. Frequency of allocation steady against penicillin of stafilokokk at patients with hron, processes, being exposed to a long antibioticotherapia, makes 60 — 95%.
Strains, moderately sensitive to penicillin, are found among gonokokk, the green streptococci, pneumococci. These strains are characterized by simultaneous resistance to others And. — to tetracycline, erythromycin, levomycetinum. The steady against penicillin green streptococci often find in the patients receiving this Ampere-second the preventive purpose.
Benzylpenicillin is highly effective at treatment of the infections caused by the beta and hemolitic and green streptococci (a septicaemia, pneumonia, endocarditises, infections of skin and soft tissues, etc.), keeps high performance at treatment of spotted and pneumococcal fevers, in most cases of gonorrhea. Benzylpenicillin is drug of the choice (the I turn) at treatment of the infections caused by the stafilokokka which are not forming some beta lactamazu and also at treatment of syphilis, listeriosis, gas gangrene. However in connection with a wide spread occurance of strains of bacteria, steady against its action, purpose of benzylpenicillin and the choice of doses shall be based on results of studying of sensitivity of activators. For ensuring effect of a penicillin therapy it is necessary to observe the mode of doses providing optimum concentration And. in an organism. Fenoksimetilpenitsillin apply in out-patient practice inside at treatment of moderately severe infections. Apply the prolonged (dyurantny) forms of benzylpenicillin to prevention of rheumatism and treatment of syphilis — Bicillinums. Also novocainic salt of benzylpenicillin has the prolonged effect.
Semi-synthetic Penicillin receives by chemical transformation 6-aminopenicillanic to - you («kernels» of a molecule of penicillin). Penitsillinazoustoychivy semi-synthetic Penicillin — Metitsillin and group of Oxacillinum is steady against the destroying action beta laktamaz (penicillinases), produced by steady activators. On a range and the mechanism of antimicrobic action, a hypotoxicity penitsillinazoustoychivy penicillin is close to benzylpenicillin, however, unlike the last, is active concerning penitsillinazoobrazuyushchy steady stafilokokk. Methicillinum, Oxacillinum and other semi-synthetic Penicillin are effective at treatment of the heavy infections of various localization caused by multiple and steady stafilokokka. However their smaller antibacterial activity concerning some species of bacteria, napr, pneumococci, meningokokk and gonokokk, in comparison with benzylpenicillin causes need of allocation and identification of the activator and definition of its antibiogramma at purpose of semi-synthetic penicillin.
Semi-synthetic Penicillin of a broad spectrum of activity — ampicillin and karbenitsillin significantly expands possibilities of treatment of the processes caused by the gram-negative activators steady to such traditional And., as tetracyclines, levomycetinum, streptomycin, etc.
Ampicillin less, than benzylpenicillin, is active concerning gram-positive cocci (staphylococcus, pneumococci, streptococci); as well as benzylpenicillin, it collapses the beta lactamhadean. To ampicillin the majority of meningokokk and gonokokk is highly sensitive. Ampicillin is highly active concerning many gram-negative bacteria (Proteus mirabilis, salmonellas, shigellas, many strains of intestinal and hemophilic sticks, klebsiyell). Pyocyanic sticks are steady against it A. Ampitsillin is inefficient at the infections caused by penitsillinazoobrazuyushchy strains of stafilokokk, gram-negative bacteria (colibacilli, proteas, a klebsiyella, an enterobakter) since he collapses this enzyme.
Ampicillin kislotoustoychiv and therefore is active both at intake, and at parenteral administration. Ampicillin often is highly effective means at treatment of the respiratory infections caused by activators, sensitive to it, especially hron, pneumonia and bronchitis, and also diseases zhelche-and urinary tract (cholecystitis, pyelonephritis, cystitis, etc.), an enterokokkovy endocarditis, the meningitis caused by meningokokka, hemophilic sticks, etc. Ampicillin has the expressed effect on salmonellas. However results wedge, uses And. at a typhoid are contradictory. Consider expedient purpose of drug at a typhoid in case of unsuccessful treatment by levomycetinum, and also at treatment of bacillicarriers.
Karbenitsillin possesses wider antimicrobic range, than ampicillin; it affects pyocyanic sticks, indolpositive strains of protiums, serratiya. However it is less active, than ampicillin, concerning colibacilli, klebsiyell and stafilokokk; it is sensitive to action to - you a gastric juice and it is entered only parenterally (intravenously or intramusculary). It is possible to create high concentration at its intravenous administration in high single doses (to 5 g) and at least, than in 4 hours that provides effect at the infections caused by the majority of strains of pyocyanic sticks. Is And. a reserve at treatment of the heavy infections caused by a pyocyanic stick, proteas of all types, colibacilli, steady against ampicillin (at damage of urinary tract, a septicaemia, a wound fever, burn sepsis). Increase in a therapeutic effectiveness of a karbenitsillin is observed at a combination to such aminoglycosides as gentamycin (see), Kanamycinum (see) and Tobramycinum. There are derivatives of a karbenitsillin for introduction inside (karindatsillin, karfetsillin) which provide smaller concentration And. in blood, than at parenteral administration, are also applied at moderately severe infections (generally at damage of urinary tract).
B Cephalosporins this group enter And., received at chemical transformation 7-aminotsefalosporanovy to - you (7-ATsK — «kernel» And. cephalosporin C) or 7-aminodezoksiatsetotsefalosporanovy to - you (7-ADTsK), being in the latter case a product of transformation of benzylpenicillin.
Cephalosporins divide into 2 groups: 1) applied parenterally (Cefaloridinum, cefalotin, cefazolin, tsefanon, tsefatsetrit, etc.) and 2) inside (Cefalexin, tsefaloglitsin); And. Cefradinum can be entered both inside, and parenterally.
Cefalotin and Cefaloridinum — the cephalosporins which are most widely applied in medical practice; they possess the broad spectrum of activity close to an action spectrum of ampicillin. The range of these And, concerning gram-positive bacteria is similar to a range of benzylpenicillin, however, unlike the last, includes penitsillinazoobrazuyushchy staphylococcus. From gram-negative bacteria the majority of strains of colibacilli, klebsiyell, protiums, shigellas, salmonellas, etc. are sensitive to cefalotin and Cefaloridinum. These And. surpass ampicillin in the relation in activity klebsiyell, however concede to it in the relation, colibacillus and enterococci. The general properties of cephalosporins is resistance to action beta laktamaz, the stafilokokk produced by polyresistant strains, sensitivity to enzymes of gram-negative activators, absence at patients of a cross allergy to penicillin (or a partial cross allergy at patients with hypersensitivity to penicillin high degree of bacterial action; the mechanism of action is based on suppression of synthesis of a cell wall of bacteria.
Cefalexin and Cefradinum on an action spectrum completely correspond to cefalotin and Cefaloridinum, but concede to them on a degree of activity concerning gram-positive and gram-negative bacteria.
The main indications to purpose of cephalosporins are respiratory infections, kidneys and urinary tract, an infection of skin and soft tissues, bones and joints, heavy is purulent - septic processes (sepsis, a septic endocarditis, meningitis) caused by sensitive microorganisms.
Aminoglycosides (aminotsiklitol) combine big group A., as natural — Streptomycin (see), Neomycinum (see), Monomycinum (see), Kanamycinum (see), gentamycin (see), sisomicin, etc., and semi-synthetic — amikacin, netilmitsin, dibekatsin, etc. These And. are characterized by the wide range of antimicrobic action including gram-positive and gram-negative bacteria, some of them are active concerning mycobacteria of tuberculosis, pyocyanic sticks, the elementary. Aminoglycosides are combined by a number of the general properties: the mechanism of antimicrobic action (inhibitors of proteinaceous synthesis of a microbic cell), the expressed bacterial action, features of pharmacokinetics (bad absorbability at use inside, weak linkng with proteins) and features of side effects (nefro-and ototoxicity, low allergenicity). The main lack of aminoglycosides (varying in a quantitative sense for various drugs) is their rather high general and specific toxicity.
Aminoglycosides resistance is defined by their inactivation the specific enzymes (phosphorylating, adeniliruyushchy, acetylating) which education is caused by R-factors. The substrate profile of enzymes for various aminoglycosides significantly differs. By search new natural And. and creations of derivatives it was succeeded to receive the drugs steady against the inactivating enzymes and, therefore, active concerning resistant forms of microorganisms.
In view of receiving new natural and semi-synthetic And. a certain revaluation of value and the place of each of representatives of this group A is necessary. in a modern antibioticotherapia of infections. Streptomycin kept the value in complex therapy of tuberculosis, at treatment of especially dangerous infections (a tularemia, plague). In combination with penicillin it is applied at treatment of the endocarditis caused by enterococci or the green streptococci, in certain cases at multi-infections. However in connection with a wide spread occurance of steady activators and opening more effective and less toxic And., use of streptomycin at pyoinflammatory processes is sharply limited, the frequency of its use decreases and at tuberculosis. Representatives of aminoglycosides of so-called firstgeneration — Neomycinum, paromomitsin are characterized by a wide range of antimicrobic action and expressed nefro-and ototoxicity. Neomycinum in this connection it is appointed only inside (an intestinal antiseptic agent) or locally has the greatest general and specific toxicity (ointments, aerosols for treatment of infections of skin, mucous, burns, wounds etc.). In view of high toxicity and presence of more effective And. (Kanamycinum, gentamycin) use of a paromomitsin (Monomycinum) is also limited; parenteral administration is recommended.
Kanamycinum is applied at therapy of the pyoinflammatory processes caused by gram-negative bacteria and steady stafilokokka. The main indications to purpose of Kanamycinum are the heavy infections (sepsis, a septic endocarditis, peritonitis, etc.) caused by colibacilli, an enterobakter, proteas, klebsiyella, including the strains steady against penicillin of a broad spectrum of activity and cephalosporins. And. it is effective at treatment acute and hron, infections of urinary tract, is antitubercular drug of the 2nd row and it is appointed at allocation of the mycobacteria steady against streptomycin, an isoniazid, PASK and other drugs.
Gentamycin, sisomicin, Tobramycinum are representatives of second generation of the aminoglycosides having the expressed advantages in comparison with earlier applied And. this group. The general feature of these drugs is their action on pyocyanic sticks, higher activity concerning other gram-negative sticks and gram-positive cocci. At concentration to 4 mkg/ml 80% of strains of a pyocyanic stick, 70% of strains klebsiyell and an enterobakter and to 100% of strains of staphylococcus are suppressed. Gentamycin resistance of microorganisms develops slowly, on multistage type. The mechanism of stability is implemented by an inactivation And. the specific enzymes of resistant microorganisms coded by R-factors. In view of distinction of a substrate profile of enzymes resistance to gentamycin and other aminoglycosides — incomplete cross. Strains, steady against gentamycin, are usually at the same time insensitive to Neomycinum, Kanamycinum, streptomycin, but keep sensitivity to new aminoglycosides (Tobramycinum, amikacin, sisomicin, etc.). The expressed synergism is noted at a combination of gentamycin with karbenitsilliny.
Value of gentamycin and other new aminoglycosides increases in treatment of the heavy infections caused by the gram-negative activators steady against other antibiotics. The main indications to their appointment are: infections of urinary tract (pyelonephritises, cystitis, uretrita); diseases of lungs and respiratory tracts (pneumonia, abscesses of a lung, empyema of a pleura, hron, bronchitis, bronchoectatic disease); surgical infection (sepsis, peritonitis, wound fever, burns, etc.); infections of newborns. Advantages of gentamycin before others And. wide range (tetracyclines, levomycetinum, semi-synthetic Penicillin, etc.) at treatment of heavy pyoinflammatory processes of a gram-negative etiology are caused by more expressed bacterial action, strong antimicrobic action, preservation of sensitivity of the majority to it a wedge, strains of so-called problem activators that provides positive takes of therapy in 80 — 90% of cases. At infections of urinary tract in 90 — 95% of cases the expressed effect at full elimination of the activator is noted. Despite nephrotoxicity, gentamycin and other aminoglycosides it is possible to apply at the infections which are followed by a renal failure; in these cases correction of doses and schemes of treatment not only on a wedge, and bacterial are necessary, for indicators, but also taking into account secretory function of kidneys. Gentamycin is successfully applied at treatment of sepsis not only at adults, but also children, including newborns. Use of gentamycin (one and in combination with penicillin) is shown at multi-infections, an endocarditis.
Restrictions of use of aminoglycosides are connected with potential from - and the nephrotoxic action depending on duration of therapy, size of doses, a condition of secretory function of kidneys and co-administration of others from - and nefrotoksichny drugs.
Discovery of new aminoglycosides with reduced specific toxicity and absorbability at introduction is possible inside that will increase practical value A. this group.
Tetracyclines combine big group natural And. (tetracycline, Oxytetracyclinum, chlortetracyclin, demetilkhlortetratsiklin) and semi-synthetic derivatives (Metacycline, doxycycline). For And. this group the following properties are characteristic: the broad spectrum of activity, to-rogo is the cornerstone oppression of synthesis of protein of a microbic cell, bacteriostatic type of action, good absorbability at intake, satisfactory portability at long introduction.
Restrictions at use of traditional natural tetracyclines (see) are connected with a wide spread occurance of resistant forms of microorganisms and emergence of by-effects. Chlortetracyclin as the most toxic And. this group it is not applied in medical practice.
Tetracycline and Oxytetracyclinum (see) are generally close on a range of antimicrobic action, average frequency of allocation of activators, steady against their action, and character of by-effects.
The semi-synthetic derivatives received on the basis of natural tetracyclines — doxycycline (Vibramycinum), Metacycline (Rondomycinum) possess wider in comparison with a natural range of antimicrobic action and the best absorbability that allows to reach big concentration And. in blood, bodies and fabrics. Metacycline and doxycycline appoint inside in much smaller doses and with big intervals, than natural tetracyclines.
Tetracyclines apply at infections of biliary tract (it is removed with bile), went. - kish. path, and also respiratory organs and urination. Tetracycline is effective also at a brucellosis, a sapa and a melioidosis, cholera, leptospirosis, rickettsioses, an ornithosis.
In all other cases tetracyclines as reserve And. appoint only at establishment of sensitivity of the allocated microorganisms to their action. Serious restriction to use of tetracyclines at treatment of children up to 5 — 8 years is their ability to collect in a bone tissue and teeth.
The principles of rational use of antibiotics
include Anti-staphylococcal antibiotics of a reserve Makrolida (see), erythromycin, Oleandomycinum, lincomycin (see), Fusidinum (see). They are effective remedies at treatment of the processes caused by steady stafilokokka, hl. obr. in case of an allergy to semi-synthetic penicillin. Lincomycin and Fusidinum have advantages over penitsillinazoustoychivy penicillin, collect in high concentration in a bone tissue, inflammatory exudate, granulations; various dosage forms of these are applied in combination with other A. Imeyutsya And. for introduction inside and parenteral use.
Carry to antitubercular antibiotics of the 1st row streptomycin (see), the 2nd row — Kanamycinum (see), Cycloserinum (see), florimitsin (see), rifampicin (see. Rifamycinums ). Rifampicin is to the semi-synthetic derivatives received on the basis of natural Rifamycinum of V. Etot A. is highly active concerning mycobacteria of tuberculosis, including steady against all to others antitubercular And. and to himiopreparata. Besides, rifampicin is highly active concerning stafilokokk, enterococci, the piogenic streptococci steady against others And., and also meningokokk and enterococci. Rifampicin forms complexes with a DNA-dependent RNA polymerase that causes its activity concerning some viruses in an experiment.
Antifungal antibiotics combine hl. obr. drugs of group of polyenes — nystatin (see), levorinum (see), Amphotericinum of B (see), etc., and also griseofulvin. General property antifungal antibiotics (see) their action on a cytoplasmic membrane of pathogenic fungi is. Drugs are active at mycoses of various etiology. Polyenes are well transferred at intake. Amphotericinum of B is applied by hl. obr. parenterally at the generalized mycoses which are not giving in to action of others And., but it has high toxicity. By certain advantages it is characterized amfoglyukamin, the drug, derivative of Amphotericinum of B, used inside, less toxic and giving less than by-effects.
The group of the substances of various structure possessing the expressed cytotoxic action on tumor cells treats antineoplastic antibiotics, being hl. obr. inhibitors of synthesis nucleinic to - t. To antineoplastic
And. (see. Antineoplastic means ) carry Actinomycinums (see); drugs of group aureolovy to - you (Olivomycinum, hromomitsin, mitramitsin); anthracyclines (daunorubitsin, doxorubicine), Carminomycinum; Streptonigrinum (Bruneomycinum); Bleomycinum. To tumors of the person which will respond to treatment antineoplastic And., carry Vilms's tumor of children and its metastasises, lymphosarcomas, reticulosarcomas, horionepitelioma, leukoses, neuroblastomas, etc.
As a rule, antineoplastic And. apply in a complex with other himiopreparata, hormones, and also with radiation therapy and an operative measure. Appears more and more new antineoplastic And., allowing to influence various tumors of the person. So, doxorubicine (adriamycin) found application at leukemias, at sarcomas and carcinomas of various localization, Bleomycinum — at epithelial carcinomas cutaneum and mucous membranes.
The combined antibioticotherapia is shown generally in the following cases: at the beginning of therapy at suspicion on the multi-infection (caused by association of activators) and a heavy current; for the purpose of strengthening of antibacterial effect at heavy infections (e.g., penicillin + streptomycin at the septic endocarditis or respiratory diseases caused by hemophilic sticks); for the prevention or delay of formation of resistant forms at purpose of macroleads, Fusidinum and other antibiotics, activators, characterized bystry distribution steady against their action; for the purpose of decrease to lay down. doses of the antibiotics having toxicity (e.g., gentamycin + karbenitsillin at treatment of a pyocyanic infection). At the choice of a combination it is necessary to avoid combinations bactericidal and bacteriostatic And.; the fixed combinations And., earlier eurysynusic abroad, as a rule, have no advantages in comparison with monotherapy and bear danger of summation of side effects.
Antibiotikoprofilaktika and a precautionary antibioticotherapia are applied at the menacing infection before development a wedge, symptoms of a disease and for the purpose of elimination of activators. To cases of preventive appointment And. carry the prevention of development of a blennorea in newborns, extensive wounds in surgeries, contact of personnel and people around with the patient with plague; epidemic of meningitis, lab. infection, the prevention of bacterial complications of viral infections, preoperative preparation, heart operation and vessels, bodies went. - kish. a path, etc.
By-effects at use of antibiotics
as a result of long-term mass use And. it is established that And. do not surpass other groups of medicinal substances in the frequency of development and expressiveness of by-effects (see. Side effects of pharmaceuticals ). Knowledge of specific features of side effect And. allows to choose drug, the most effective and harmless to this patient. The by-effects caused And., it is possible to divide into the allergic reactions, toxic reactions and by-effects connected with antimicrobic action And.
Allergic reactions arise in response to introduction And., their development does not depend on the entered dose, but amplifies at its increase. The allergic phenomena arise after the first introduction And. or a sensitization at repeated introductions is result. Most often the allergy is shown by a skin itch, a small tortoiseshell, rash, rhinitis, conjunctivitis; also heavy displays of an allergy in the form of an acute anaphylaxis, a Quincke's disease of a throat are possible.
Allergic reactions cause many And. The allergic phenomena need to be differentiated from a wedge, the displays of a disease caused by co-administration of other drugs, and also the solvents (e.g., novocaine) applied at introduction A. Naiboley often allergic reactions arise at topical administration (ointments, aerosols etc.), is more rare — at parenteral administration of A. Osobenno allergic reactions at individual hypersensitivity are serious to this
And. or group. An allergy to And. can have cross character with other allergens, including medicinal. Hypersensitivity to And. depending on group A. it is observed at 1 — 10% of patients, but the acute anaphylaxis (see) meets seldom (isolated cases on one million patients subjected to treatment And.). The most often allergic phenomena arise at treatment And. groups of penicillin (a floor at synthetic penicillin is more rare), and also streptomycin, tetracycline, novobiocin Sick with an allergy to penicillin in the anamnesis to enter this And. it is impossible; it is necessary to consider also allergic reactions to other medicinal substances. Prevention and treatment of other allergic reactions are based on their differentiation from the toxic phenomena and symptoms of a basic disease, clarification of the anamnesis of the patient. It is necessary to avoid use of combinations of Ampere-second possible allergenic action, not to apply locally And., which should be entered parenterally. At development of allergic reactions for bystry desensitization it is necessary to appoint antihistaminic substances, corticosteroids; at a penicillin therapy — penicillinase (see).
Toxic reactions of various degree and character are inherent to all groups A., their expressiveness is connected with the size of the entered dose. The toxic phenomena are caused And., the accompanying impurity, products of destruction and metabolism And. in an organism. Expressiveness of toxic reactions amplifies at disturbance of blood circulation, secretory function of the kidneys and a liver promoting accumulation and cumulation And. in an organism. To a row A. the neurotoxic phenomena are inherent: action on the VIII pair of cranial nerves (aminoglycosides), an optic nerve (streptomycin, levomycetinum, Cycloserinum, polymyxins), paresthesias, hypostasis, headaches, dizzinesses (polymyxins, Streptomycin, Cycloserinum, Amphotericinum of B), defeats of c. N of page (Cycloserinum, griseofulvin, Amphotericinum of B, Penicillin, streptomycin), neuromuscular blockade (aminoglycosides, polymyxin). The nephrotoxic phenomena can be observed at use of polymyxins, Amphotericinum of B, aminoglycosides, griseofulvin, Ristomycinum, some penicillin (Methicillinum), cephalosporins (Cefaloridinum), Ristomycinum. The hepatotoxic action meets less often, it is peculiar to Amphotericinum of B, lincomycin, tetracyclines, novobiocin. Action on went. - kish. a path (nausea, vomiting, anorexia, pains in a stomach, ponosa etc.) can be observed at administration of tetracycline, erythromycin, griseofulvin, Amphotericinum of B, Fusidinum and others And., what usually does not interfere with continuation of therapy. At introduction in lincomycin and especially clindamycin there can be heavy pseudomembranous coloenterites, sometimes from the death. The Gematotoksichesky phenomena of various weight are established for limited number A.: hypoplastic anemia — at use of levomycetinum and Amphotericinum In; hemolitic anemias — levomycetinum, streptomycin; aplastic anemias — levomycetinum. As a rule, the gematotoksichesky phenomena have reversible character, except severe damages of marrow (aplastic anemias) at use of levomycetinum.
Embriotoksichesky action And. it is connected with their penetration through a placental barrier and impact on a fruit. Cases of defeat of hearing and kidneys of newborns at treatment are described pregnant with aminoglycosides, influence on a skeletoobrazovaniye and an odontosis under the influence of tetracyclines. For the prevention of possible toxic action on a fruit for 3 — 6 weeks before childbirth appointment is forbidden to pregnant women of levomycetinum and tetracycline, novobiocin, aminoglycosides.
The by-effects connected with antimicrobic action And., can be expressed in a hospitalism, dysbacterioses (see), reactions of a bacteriolysis (see. Yarisha — Gerksgeymera — Lukashevich reaction ), impact on immune mechanisms of the patient. Superinfections of endogenous and exogenous character are connected with emergence of the process caused by apatogenous or opportunistic microorganisms (staphylococcus, pyocyanic and intestinal sticks, anaerobe bacterias, pathogenic fungi, etc.). Weight of a current of superinfections and their localization can be various (defeats of c. the N of page, uric ways, went. - kish. path, mucous membranes, skin etc.). The special group of complications is made by the candidiases caused by yeast-like fungi of the sort Candida which strengthened reproduction can be observed at use And. a broad spectrum of activity, breaking the developed microbic biocenoses (see. Candidiasis ). In the main way of the prevention and decrease in frequency of the by-effects caused And., their rational appointment, the choice of the most effective and harmless is And. on the basis of a complex of clinical laboratory data, use of optimum doses and methods of introduction.
Table. Range, mechanism and type of antimicrobic action of the main antibiotics and method of their introduction
Bibliography: Gayle E., etc. Molecular bases of action of antibiotics, the lane with English, M., 1975, bibliogr.; Ermolyeva 3. B. Antibiotics, Interferon, Bacterial polysaccharides, M., 1968, bibliogr.; Cat's P. N. and d river. Antibiotics, M., 1970, bibliogr.; Klimov A. N. Penicillin and cephalosporins, L., 1973, bibliogr.; To zhy Beck and T., Kovshyk-Gindifer 3. and To at-rylovich Century. Antibiotics, the lane with polsk., t. 1 — 2, Warsaw, 1969; Navashin S. M. and Fomina I. P. Semi-synthetic Penicillin, M., 1974; they, Reference book on antibiotics, M., 1974; Navashin S. M., Fomina I. P. and With and z y to and Yu. O N. Antibiotics of group of aminoglycosides, M., 1977; Sazykin Yu. O. Antibiotics as inhibitors of biochemical processes, M., 1968, bibliogr.; about N e, Biochemical mechanisms of resistance to inhibitors of proteinaceous synthesis, M., 1972; Antibiotica-Fibel, hrsg. v. H. Otten u. a., Stuttgart, 1976, Bibliogr.; Glas-b at I. S. Encyclopaedia of antibiotics, N.Y., 1976.
S. M. Navashin.