1) endogenous - develops as a result of the activation of conditionally pathogenic microorganisms that normally exist in the human body (for example, in the oral cavity, intestines, on the skin, etc.); 2) exogenous - occurs as a result of infection by microorganisms that come from outside. Exogenous infection can be domestic (the disease began before admission to the hospital) and hospital or nosocomial (occurs 48 hours or more after admission to the hospital, characterized by resistance of microorganisms to many antibiotics). Medicine Antimicrobial agents can have: 1. bactericidal effect - characterized by significant changes in cell membranes, intracellular organelles, irreversible metabolic disorders of microorganisms that are incompatible with life and lead to their death; 2. bacteriostatic action - characterized by inhibition of the development and growth of microorganisms; 3. mixed action - characterized by the development of a bacteriostatic effect in small doses and a bactericidal effect - in large doses. Classification of antimicrobial drugs depending on the application: 1. Disinfectants- are used for indiscriminate destruction of microorganisms outside the macroorganism (on care items, bedding, tools, etc.). These drugs act bactericidal, have a pronounced antimicrobial activity, and are toxic to the macroorganism. 2. Antiseptics - used for indiscriminate destruction of microorganisms on the surface of mucous membranes, serous membranes and skin. They should not be very toxic and cause severe side effects, as they are able to penetrate these shells. They have a bactericidal and bacteriostatic effect. 3. Chemotherapeutic agents - used to destroy microorganisms in the human body, should have a selective effect (act only on the microorganism, without violating the function of the macroorganism). The main principle of chemotherapy is to achieve and maintain the required concentration of the drug at the site of injury. CHEMOTHERAPEUTIC DRUGS Depending on the origin, chemotherapeutic agents are divided into 2 large groups: 1. Chemotherapeutic agents of synthetic origin 2. Antibiotics - chemotherapeutic agents of biological origin and their synthetic analogues. Synthetic antimicrobial agents 1. Sulfanilamide agents 2. Nitrofurans 3. 8-Hydroxyquinoline derivatives 4. Quinolones 5. Fluoroquinolones 6. Quinoxaline derivatives grounds. Many microorganisms, as well as humans, use ready-made folic acid(sulfonamides have no effect on them). And some microorganisms use endogenous folic acid, but in the presence of sulfonamides, they mistakenly include them in its synthesis. Defective vitamin BC is synthesized, which disrupts the synthesis of RNA and DNA and the reproduction of microorganisms. In foci of necrosis, purulent wounds (tissues containing a lot of para-aminobenzoic acid), the effect of sulfonamides is reduced, with the exception of topical preparations containing silver (silver ions themselves have a bactericidal effect). View pharmacological action - bacteriostatic. Spectrum of antimicrobial action: gram-negative enterobacteria (salmonella, shigella, klebsiella, escherichia), gram-positive cocci, chlamydia, actinomycetes, proteus, influenza bacillus, toxoplasma, malaria plasmodia. Silver-containing preparations are also active against Pseudomonas aeruginosa, Candida. Currently, staphylococci, streptococci, pneumococci, meningococci, gonococci, enterobacteria have acquired resistance to sulfonamides. The causative agent of whooping cough, enterococci, Pseudomonas aeruginosa, anaerobes are insensitive to them. Classification I. Drugs well absorbed in the gastrointestinal tract: 1) drugs of medium duration of action - norsulfazol, etazol, sulfadimidine (sulfadimesin), sulfadiazine (sulfazine), urosulfan; 2) long-acting drugs - sulfadimethoxine, sulfopyridazine; 3) super-long-acting drugs - sulfalene; 4) combined preparations - sulfatone, co-trimoxazole. II. Drugs that are poorly absorbed in the gastrointestinal tract: sulgin, ftalazol. III. Preparations that have a local effect: sulfacyl - sodium, sulfazine silver salt, sulfadiazine silver. Principles of therapy: sulfonamides are drugs of a concentration type of action (their concentration in the microorganism should be greater than the concentration of para-aminobenzoic acid). If this rule is not observed, sulfa drugs will not have their effect, in addition, the number of resistant strains of microorganisms will increase. Therefore, sulfanilamide drugs are prescribed first in a loading dose, then, when the required concentration of the drug is reached, in a maintenance dose, subject to certain intervals between injections. In addition, in purulent, necrotic foci rich in para-aminobenzoic acid, sulfonamides are inactive. I. Drugs that are well absorbed in the gastrointestinal tract Features of pharmacokinetics: absorbed by 70-100%, penetrate well into tissues, through the blood-brain barrier (except for sulfadimethoxine), rather strongly bind to plasma proteins (50-90%). Long-acting and ultra-long-acting drugs undergo glucuronidation, and short- and medium-acting drugs are metabolized in the liver by acetylation (except for urosulfan) with the formation of inactive metabolites that are excreted in the urine. Renal excretion of acetylates increases with alkaline urine, and in an acidic environment they precipitate, which leads to crystalluria. Therefore, during treatment with sulfonamides, the use of acidic foods is not recommended. 1) the duration of the effect of drugs with an average duration of action: on the 1st day - 4 hours, by 3-4 days - 8 hours, the loading dose is 2 g, the maintenance dose is 1 g after 4-6 hours. 2) the duration of the effect of long-term drugs action - 1 day, loading dose - 1-2 g, maintenance dose - 0.5 -1 g 1 time per day. 3) the duration of the effect of super-long-acting drugs is 24 hours or more, the loading dose is 1 g, the maintenance dose is 0.2 g 1 time per day. II. Drugs that are poorly absorbed in the gastrointestinal tract are used for gastrointestinal infections on the first day 6 times a day, then according to the scheme, reducing the dose and frequency of administration. III. Preparations that have a local effect are used in the form of solutions, powders or ointments in ophthalmic practice (treatment and prevention of blennorrhea, conjunctivitis, corneal ulcers), for the treatment of wounds, burns. Preparations combined with trimethoprim Mechanism of action of trimethoprim: inhibits dehydrofolate reductase, which is involved in the conversion of folic acid into its active form - tetrahydrofolic acid. Spectrum of action: staphylococci (including some methicillin-resistant), pneumococci (resistant according to a multicenter study 32.4%), some streptococci, meningococci, Escherichia coli (30% of strains are resistant), influenza bacillus (according to a multicenter study resistant 20.9 %) strains are resistant), Klebsiella, Citrobacter, Enterobacter, Salmonella. Combined preparations compared to monopreparations have the following properties: - have a wider spectrum of action, because they also affect microorganisms that use ready-made folic acid (pneumocysts, Haemophilus influenzae, actinomycetes, legionella, etc.); - have a bactericidal effect; - act on microorganisms resistant to others sulfa drugs; - are more pronounced side effects, because affect the processes occurring in the human body, are contraindicated in children under 2 years of age. The duration of action of combined preparations is 6-8 hours, the loading dose is 2 g, the maintenance dose is 1 g 1 time per day. side effects 1. allergic reactions. 2. Dyspepsia. 3. Nephrotoxicity (crystalluria, obstruction of the renal tubules) with the use of drugs with a short and medium duration of action, not typical for urosulfan. Decreases as a result of the use of a large amount of alkaline liquids, tk. alkaline environment prevents precipitation of sulfonamides. 4. Neurotoxicity ( headache, disorientation, euphoria, depression, neuritis). 5. Hematotoxicity ( hemolytic anemia thrombocytopenia, methemoglobinemia, leukopenia). 6. Hepatotoxicity (hyperbilirubinemia, toxic dystrophy). 7. Photosensitization. 8. Teratogenicity (combined drugs). 9. Local irritating effect (local preparations). 10. Dysfunction of the thyroid gland. Indications for use Due to low efficiency, high toxicity, frequent secondary resistance, non-combined drugs in systemic diseases are used very limitedly: for pneumocystis pneumonia, nocardiosis, toxoplasmosis (sulfadiazine), malaria (with P. falciparum resistance to chloroquine), for the prevention of plague. Combined preparations are indicated for the following diseases: 1. Infections of the gastrointestinal tract (shigellosis, salmonellosis, etc., caused by susceptible strains). 2. Infections urinary tract (cystitis, pyelonephritis). 3. Nocardiosis. 4. Toxoplasmosis. 5. Brucellosis. 6. Pneumocystis pneumonia. Drug Interactions 1. Sulfonamides, by displacing from protein binding and / or weakening metabolism, enhance the effects of indirect anticoagulants, anticonvulsants, oral hypoglycemic agents and methotrexate. 2. Indomethacin, butadione, salicylates increase the concentration of sulfonamides in the blood, displacing them from their association with proteins. 3. When used together with hemato-, nephro- and hepatotoxic drugs, the risk of developing the corresponding side effects increases. 4. Sulfonamides reduce the effectiveness of estrogen-containing contraceptives. 5. Sulfonamides increase the metabolism of cyclosporine. 6. The risk of developing crystalluria increases when combined with urotropin. 7. Sulfonamides weaken the effect of penicillins. Average daily doses, route of administration and forms of release of sulfonamides Drug Forms of release Route Average daily doses Sulfamidimezin Tab. 0.25 and 0.5 g each Inside 2.0 g for the 1st dose, then 1.0 g every 4-6 hours Etazol Tab. 0.25 and 0.5 g each; amp. Inside, in / in Inside - 2.0 g per 1st for 5 and 10 ml of 5 and 10% solution (slowly) reception, then 1.0 g every 4-6 hours; IV - 0.5 - 2 g every 8 hours. Sufadimethoxin Tab. 0.2 g inside 1.0-2.0 g on the 1st day, then 0.5-1.0 g 1 time / day Sulfalen Tab. 0.2 g inside 1.0 g on the 1st day, then 0.2 g 1 time / day or 2.0 1 time / week Sulfadiazine 1% ointment in tubes of 50 g Locally 1-2 times / day -trimoxazole Tab. 0.2 g each, 0.48 and 0.96 Inside, in / in Inside -0.96 g 2 times / day, g; flak. Sir. 0.24 g/5 ml; in / in - 10 mg / kg / day in 2-3 amps. 5 ml each (0.48 g) Nitrofurans furacilin, nitrofurantoin (furadonin), furazidin (furagin), furazolidone Mechanism of action: nitrofurans in their composition have a nitro group, which is restored in microorganisms and passes into an amino group. Thus, nitrofurans are hydrogen ion acceptors, which disrupts the metabolism of microbial cells, reduces the production of toxins and the risk of intoxication. In addition, they reduce the activity of certain enzymes, resistance to phagocytosis, and also disrupt the synthesis of DNA of microorganisms. Effective in the presence of pus and acidosis. Type of pharmacological action: they have a bacteriostatic, and in large doses - a bactericidal effect. Spectrum of antimicrobial activity: gram-positive and gram-negative microorganisms: streptococci, staphylococci, Klebsiella pneumoniae, Escherichia and dysentery coli, etc. ; candida, protozoa: trichomonas, giardia, chlamydia (furazolidone). Pseudomonas aeruginosa, Proteus, Providence, Serrations, Acinetobacter are resistant to them. Resistance to nitrofurans develops slowly. Features of pharmacokinetics: well absorbed from the lumen of the gastrointestinal tract, do not create high concentrations in body tissues and bloodstream, half-life - 1 hour. Furadonin, furagin create an effective concentration in the urine, can color it rusty-yellow or brown (with kidney failure are contraindicated, because they can accumulate), furazolidone is metabolized in the liver, excreted in the bile and accumulates in high concentrations in the intestinal lumen (contraindicated in liver failure). Side effects 1. Gastrointestinal disorders (nausea, vomiting, lack of appetite). 2. Dysbacteriosis (recommended to take with nystatin). 3. Neurotoxicity (headache, dizziness, drowsiness, polyneuropathy). 4. Avitaminosis (taken together with B vitamins). 5. Allergic reactions. 6. Hematotoxicity (leukopenia, anemia). Application - treatment of wounds (furatsilin). The remaining nitrofurans are prescribed after meals at 0.1-0.15 g 3-4 times a day for the following diseases: - urinary tract infections (furadonin, furagin, as they are uroseptics); - dysentery, enterocolitis (nifuroxazide, furazolidone); - trichomoniasis, giardiasis (furazolidone); - alcoholism (furazolidone disrupts the metabolism of ethyl alcohol, causes intoxication, contributes to the formation of a negative attitude towards alcohol intake). Drug interactions 1. Quinolones reduce the effectiveness of furadonin and furagin. 2. The risk of hematotoxicity increases when used together with chloramphenicol. 3. When using furazolidone (inhibits monoamine oxidase) with sympathomimetics, tricyclic antidepressants, products containing tyramine (beer, wine, cheese, beans, smoked meats), a sympathetic-adrenal crisis may develop. Average daily doses, route of administration and forms of release of nitrofurans Preparation Forms of release Route Average daily doses Furodonin Tab. 0.05 and 0.1 g, inside 0.05 - 0.1 g 4 times / day 0.03 g (for children) Furagin Tab. 0.05 g each Inside 0.1-0.2 g 3-4 times / day Nufuroxazide Tab. 0.2 g each; 4% syrup Inside 0.2 g 4 times / day Furazolidone Tab. 0.05 g each; flak. 150 Inside 0.1 g 4 times / day ml, sod. 50 g grains d/prep. susp. d / ingestion Derivatives of 8-hydroxyquinoline 5-NOC (nitroxoline), intetrix, chlorquinaldone Mechanism of action: inhibit protein synthesis, nitroxoline reduces the adhesion of Escherichia coli to the urinary tract epithelium. The type of pharmacological action is bacteriostatic. Spectrum of antimicrobial action: Gram-positive cocci, Gram-negative bacteria of the Enterobacteriaceae family (Escherichia, Salmonella, Shigella, Proteus), fungi of the Candida genus, amoeba, Giardia. Features of pharmacokinetics: nitroxoline is well absorbed in the lumen of the gastrointestinal tract, chlorquinaldone is not absorbed and creates an effective concentration there. Nitroxoline is not metabolized, creating high concentrations in the urine. When using nitroxoline, staining of urine and feces in a saffron yellow color is possible. Side effects 1. Peripheral neuritis (chlorquinaldone). 2. Neuritis optic nerve (usually chlorquinaldone). 3. Allergic reactions. 4. Dyspeptic disorders. Application: currently not used in most countries. Nitroxoline is more commonly used as a reserve drug for urinary tract infections. 1. Infections of the urinary tract (nitroxoline, used orally at 0.1, in severe cases - up to 0.2 g 4 times a day); 2. Intestinal infections (dysentery, salmonellosis, amebiasis, dysbacteriosis and others), drugs that are not absorbed from the gastrointestinal tract are used - intetrix, chlorquinaldone (0.2 g 3 times a day). Average daily doses, route of administration and forms of release of nitroxoline Preparation Forms of release Route Average daily doses of Nitroxoline Tab. 0.05 g each Inside (for 1 0.1-0.2 g 4 times / day, an hour before meals) Quinolones / Fluoroquinolones Classification of quinolones I generation nalidixic acid (nevigramon) oxolinic acid (gramurin) pipemidic acid (palin) II generation ciprofloxacin (ciprolet) pefloxacin (abactal) norfloxacin ofloxacin (tarivid) III generation sparfloxacin levofloxacin IV generation moxifloxacin Mechanism of action: inhibit the enzymes DNA-gyrase, topoisomerase IV and disrupt the synthesis of DNA of microorganisms. The type of pharmacological action is bactericidal. Spectrum of antimicrobial action. Quinolones act on gram-negative microorganisms of the Enterobacteriace family (Salmonella, Shigella, Escherichia, Proteus, Klebsiella, Enterobacter), Haemophilus influenzae and Neisseria. Staphylococcus aureus and Pseudomonas aeruginosa are affected by pipemidic and oxolinic acids, but this is of no practical importance. Fluoroquinolones (drugs of II-IV generation), in addition to the above microorganisms, are active against staphylococci, serrations, providence, citrobacter, moraxella, pseudomonads, legionella, brucella, yersinia, listeria. In addition, preparations of III and especially IV generation are highly active against pneumococci, intracellular pathogens (chlamydia, mycoplasmas), mycobacteria, anaerobes, and also act on microorganisms resistant to quinolones of I-II generation. Enterococci, corynebacteria, campylobacter, helicobacter pylori, and ureaplasma are less sensitive to fluoroquinolones. Pharmacokinetics Well absorbed in the gastrointestinal tract, the maximum concentration in the blood is created after 1-3 hours. Quinolones do not create an effective concentration in the bloodstream, body tissues. Oxolinic and nalidixic acids are actively metabolized and excreted by the kidneys in the form of active and inactive metabolites, pipemidic acid is excreted in the urine unchanged. Frequency rate of introduction - 2-4 times a day. Fluoroquinolones create high concentrations in the organs and tissues of the body, inside cells, some pass through the blood-brain barrier, creating an effective concentration there (ciprofloxacin, ofloxacin, pefloxacin, levofloxacin). Frequency rate of introduction - 1-2 times a day. Pefloxacin is actively biotransformed in the liver. Lomefloxacin, ofloxacin, levofloxacin are metabolized to a small extent, mainly in the kidneys. Excreted with urine, a smaller part - with feces. Side effects 1. Dyspeptic disorders. 2. Neurotoxicity (headache, insomnia, dizziness, ototoxicity, visual impairment, paresthesia, convulsions). 3. Allergic reactions. 4. Hepatotoxicity (cholestatic jaundice, hepatitis - drugs of the first generation). 5. Hematotoxicity (leuko-, thrombocytopenia, hemolytic anemia - drugs of the first generation). 6. Arthralgia (a species-specific side effect was experimentally revealed, which manifests itself in the form of disorders in the cartilaginous tissue in puppies of Beagle dogs), myalgia, tendovaginitis - fluoroquinolones (very rarely). 7. Crystalluria (rarely fluoroquinolones). 8. Mucosal candidiasis oral cavity and vagina. 9. Prolongation of the Q-T interval on the ECG (fluoroquinolones). The use of Quinolones is mainly as uroseptics (except for acute pyelonephritis), less often for intestinal infections: shigellosis, enterocolitis (nalidixic acid). Fluoroquinolones are a reserve means - they should be used mainly when other highly active antibiotics are ineffective. a wide range actions in the following pathological conditions: 1. Urinary tract infections (cystitis, pyelonephritis). 2. Infections of the skin, soft tissues, bones, joints. 3. Sepsis. 4. Meningitis (ciprofloxacin). 5. Peritonitis and intra-abdominal infection. 6. Tuberculosis (with drug resistance to other drugs, ciprofloxacin, ofloxacin, lomefloxacin are used as part of combination therapy). 7. Infections of the respiratory tract. 8. Prostatitis. 9. Gonorrhea. 10. Anthrax. 11. Intestinal infections (typhoid fever, salmonellosis, cholera, yersiniosis, shigellosis). 12. Treatment and prevention of infectious diseases in patients with immunodeficiency. Contraindicated: pregnant, lactating, children and adolescents under 18 years of age (during the formation of the skeleton), with allergies to quinolones. With mild infections, they are not advisable to prescribe. Drug interactions 1. Form chelate complexes with antacids, which reduces the absorption of drugs. 2. Non-steroidal anti-inflammatory drugs, nitroimidazole derivatives, methylxanthines increase the risk of developing neurotoxic side effects. 3. Antagonize with nitrofurans. 4. The use of pipemidic acid, ciprofloxacin, norfloxacin, pefloxacin increases the toxicity of methylxanthines due to a decrease in their elimination from the body. 5. When using quinolones, ciprofloxacin, norfloxacin with indirect anticoagulants, it is necessary to adjust the dose of the latter, as their metabolism is disturbed and the risk of bleeding increases. 6. When administered with antiarrhythmics, monitor the duration of the QT interval. 7. When used together with glucocorticoids, the risk of tendon rupture increases. Average Daily Doses, Route of Administration, and Formulations of Quinolones/Fluoroquinolones Drug Formulation Route Average Daily Doses Nalidix Caps. 0.5 g, tab. 0.5 g inside 0.5 g - 1 g 4 times / day oxolinic acid Tab. 0.25 g inside 0.5 g - 0.75 g 2 times / day. acid Ciprofloxacin Tab. 0.25 g, 0.5 g, 0.75 g each; Inside, in / in, Inside - 0.25 - 0.75 g 2 vials. 50 and 100 ml of 0.2% r- locally times / day, acute. gonorrhea - ra; amp. 10 ml of 1% solution 0.5 g once; i / v - 0.4 (concentrate); 0.3% eye., - 0.6 2 times / day, ear. Drops, eyes. ointment topically - 4-6 times / day Ofloxacin Tab. 0.1 g, 0.2 g; Inside, in / in, Inside - 0.2 - 0.4 g 2 vials. 0.2% solution; 0.3% eye., local times / day, acute. gonorrhea - ear. drops, eyes ointment 0.4 g once; IV - 0.4 - 0.6 1-2 times / day, locally - 4-6 times / day Norfloxacin Tab. 0.2 g, 0.4 g, 0.8 g each; Inside, Inside - 0.2 - 0.4 g 2 vial. 5 ml of 0.3% solution locally times / day, acute. gonorrhea - (eye, ear drops) 0.8 g once; locally

Antimicrobials

- chemotherapeutic substances, preferably affecting the intensity of various microorganisms.
Classification characterizing antimicrobial agents. Antimicrobial drugs are distinguished by activity, by type of agreement with the cell of microorganisms and by acid resistance.

According to the type of activity, antibacterial agents are divided into three types: antifungal, antibacterial and antiprotozoal.

According to the type of agreement with the cell of microorganisms, two types of medicines are distinguished:
bactericidal- a drug that disrupts the functions of a bacterial cell or its unity, destroying microorganisms. Such drugs are prescribed for debilitated patients and for severe infections;
Bacteriostatic- a powder that blocks the repetition, or cell fragmentation. These agents are used by unimpaired patients for minor infections.
According to acid resistance, antimicrobial drugs distinguish between acid-resistant and acid-resistant. Acid-resistant drugs are taken internally, and acid-resistant drugs are designed for parenteral use, i.e. without entering the gastrointestinal tract.

Types of antimicrobial agents:
1. Decontamination preparations: used to eliminate bacteria located in environment;
2. Antiseptic: finds its application in order to destroy microbes that are located on the plane of the skin;
3. Chemotherapeutic substances: used to eliminate bacteria located inside the human body:
Disinfectants are used to destroy bacteria that are located in the environment;
An antiseptic (antibiotic, sulfanilamide) is used to destroy microbes located on the plane of the mucous membranes and skin. Such drugs are used externally;
Chemotherapeutic drugs: antibiotic, non-biological antibacterial substances (sulfanilamide, quinolone, fluoroquinolone, as well as quinoxaline and nitroimidazole derivatives).

Preparations

There are two types antimicrobials- sulfonamides and antibiotics.
- white or yellowish powders, odorless and colorless. These medicines include:
Streptocid (used for the course of therapy of epidemic cerebrospinal meningitis, tonsillitis, cystitis, with preventive purposes wound microbes, for the healing of purulent wounds, ulcers and burns);
Norsulfazol (prescribed for pneumonia, meningitis, gonorrhea, sepsis);
Inhalipt (finds use as an antiseptic for laryngitis, tonsillitis, purulent stomatitis and pharyngitis);
Ftalazol (helps with constant facts of dysentery, gastroenteritis and colitis);
Furacilin (prescribed for anaerobic disease, boils of the external auditory opening, conjunctivitis, blepharitis);
Fastin (used for burns of I-III degrees, pyoderma, purulent skin lesions).
Antibiotics are inseparable substances that are formed by bacteria and other advanced plant organisms, characterized by the ability to destroy bacteria. The following antibiotics are distinguished:
Penicillin (helps for a course of therapy for sepsis, phlegmon, pneumonia, meningitis, abscess);
Streptomycin (used for pneumonia, urinary tract infection, peritonitis);
Microplast (used for scratches, cracks, abrasions, wounds);
Synthomycin (used to heal wounds and ulcers);
Antiseptic paste (used to eliminate inflammatory movements in the mouth and during interventions by surgeons in the oral cavity);
Antiseptic powder (used for the treatment of ulcers, wounds, burns and boils);
A bactericidal plaster is used as an antiseptic dressing for minor wounds, cuts, abrasions, burns, ulcers;
Gramicidin (used to eliminate wounds, burns, purulent skin diseases);
Gramicidin (tablets) is used in the destruction of the oral mucosa, with stomatitis, tonsillitis, pharyngitis and gingivitis.
Antibacterial panaceas are used during the rehabilitation of infectious infections of the human or animal body. Treatment with antimicrobial agents is carried out strictly under the supervision of the attending physician.

Allocate: 1) drugs that disrupt the metabolism of folic acid; 2) fluoroquinolones; 3) nitroimidazole derivatives; 4) 8-aminoquinoline derivatives; 5) nitrofurans; 6) quinoxaline derivatives; 7) oxazolidinones.

In 1939, G. Domagk (Germany) received the Nobel Prize for the discovery of the antibacterial effect of prontosil (red streptocide).

Sulfonamides similar in structure to para-aminobenzoic acid (PABA), which is part of folic acid (pteridine-PABA-glutamic acid). The addition of pteridine to PABA and the formation of dihydropteridine occur under the influence of dihydropteroate synthase. The affinity of sulfonamides for dihydropteroate synthase is significantly higher than that of PABA. Therefore, sulfonamides displace PABA from the compound with pteridine, inhibit dihydropteroate synthase and thus disrupt the synthesis of folic and dihydrofolic acids (Fig. 66).

Sulfonamides have a bacteriostatic effect. Effective against streptococci, pneumococci, Haemophilus influenzae, chlamydia, nocardia.

Gonococci, meningococci, Escherichia coli, Brucella, Vibrio cholerae are less sensitive to sulfonamides. Many strains of shigella and staphylococci are resistant. Sulfonamides have a depressing effect on Toxoplasma and Plasmodium malaria .Apply sulfonamides in toxoplasmosis, nocardiosis, conjunctivitis caused by microorganisms sensitive to sulfonamides; less often when acute infections respiratory and urinary tract, intestines.

Sulfadiazine (sulfazine), sulfaetidol (etazol), sulfadimmine (sulfadimezin) are administered orally 4-6 times a day, sulfadimethoxine - 1 time per day, sulfalene - 1 time per week.

Sulfacetamide-sodium (sulfacyl-sodium) is used in solution in the form of eye drops for conjunctivitis, blepharitis 4-6 times a day.

Sulfacarbamide (urosulfan) is largely excreted unchanged by the kidneys. Assign inside for acute urinary tract infections 3-4 times a day.

Phthalylsulfathiazole (phthalazol) and sulfaguanidine (sulgin) are poorly absorbed into gastrointestinal tract. Assign inside with intestinal infections 4-6 times a day.

Sulfadiazine silver salt is used as an ointment (sulfargin) to treat infected burns and wounds.

Side effects of sulfonamides: nausea, vomiting, diarrhea, crystalluria, disorders of the blood system, liver function, peripheral neuritis, hypersensitivity reactions (hyperthermia, urticaria, joint pain, Stevens-Johnson syndrome).

Anti-tuberculosis drugs, classification, advantages and disadvantages of individual drugs, indications for use, undesirable effects and their prevention. The tactics of using anti-tuberculosis drugs.

There are anti-tuberculosis drugs of the I and II series.

Anti-tuberculosis drugs of the first line include isoniazid, rifampicin, ethambutol. They are used in combination for a long time. This increases the effectiveness of treatment and prevents the development of resistant forms of Mycobacterium tuberculosis.

With insufficient effectiveness of the drugs of the first line, anti-tuberculosis drugs of the second line are additionally prescribed - pyrazinamide, streptomycin, cycloserine, thiacetazone, lo-mefloxacin, etc.

Isoniazid - synthetic compound; isonicotinic acid hydrazide (GINK; ftivazid, metazid belong to the same group).

It acts selectively on Mycobacterium tuberculosis (it disrupts the synthesis of mycolic acids in the cell wall). It has a bactericidal effect on dividing mycobacteria and a bacteriostatic effect on resting mycobacteria.

It is effective against mycobacteria, which are not only extracellular, but also inside cells (for example, in macrophages), as well as in caseous foci. The drug is administered orally or intramuscularly.

Side effects of isoniazid: peripheral neuritis (impairs pyridoxine metabolism), optic neuritis, insomnia, agitation, psychotic reactions, liver dysfunction, hypersensitivity reactions.

Rifampicin - broad spectrum antibiotic. It has a bactericidal effect on Mycobacterium tuberculosis, disrupting RNA synthesis. Effective against intracellular forms of bacteria and mycobacteria in caseous foci. The drug is administered orally or intravenously.

Mycobacteria rapidly develop resistance to rifampicin. Therefore, the drug is prescribed only in combination with other anti-TB drugs.

Side effects of rifampicin: nausea, dizziness, ataxia, liver dysfunction, allergic reactions, reddish-brown staining of saliva, sweat, urine. Rifampicin is an inducer of microsomal liver enzymes, therefore, with the simultaneous administration of other drugs, the effectiveness of these drugs may decrease.

Ethambutol- Synthetic anti-tuberculosis agent. It acts tuberculostatically. Resistance of mycobacteria to ethambutol develops slowly. The drug is prescribed inside.

Side effects: nausea, headache, optic neuritis (color vision is impaired), arthralgia, skin rashes.

Tuberculosis treatment is carried out in courses for 6 or 8 months. In the first 2 months, isoniazid, rifampicin, pyrazinamide are prescribed together; if necessary, add streptomycin or ethambutol. Subsequently, isoniazid and rifampicin are continued.

Antibacterial medicines- these are derivatives of the vital activity of microorganisms or their semi-synthetic and synthetic analogues that can destroy the microbial flora or inhibit the growth and reproduction of microorganisms. Antibacterial therapy is one of the types of chemotherapy and requires the right approach to treatment based on the kinetics of absorption, distribution, metabolism and excretion of drugs, on mechanisms of therapeutic and toxic action of drugs.

Considering the way in which the data medications fight the disease, then the classification of antibiotics according to the mechanism of action divides them into: drugs that disrupt the normal functioning of cell membranes; substances that stop protein and amino acid synthesis; inhibitors that destroy or suppress the synthesis of cell walls of all microorganisms. According to the type of effect on the cell, antibiotics can be bactericidal and bacteriostatic. The former kill harmful cells very quickly, the latter slow down their growth and prevent reproduction. The classification of antibiotics by chemical structure takes into account groups according to the spectrum of action: beta-lactam (natural, semi-synthetic, broad-spectrum substances), which affect microbes in different ways; aminoglycosides that affect bacteria; tetracyclines that suppress microorganisms; macrolides that fight gram-positive cocci, intracellular irritants, which include chlamydia, mycoplasmas, etc.; ansamycins, especially active in the treatment of gram-positive bacteria, fungi, tuberculosis, leprosy; polypeptides that stop the growth of gram-negative bacteria; glycopeptides that destroy the walls of bacteria, stopping the synthesis of some of them; anthracyclines used in neoplastic diseases.

According to the mechanism of action, antibacterial agents are divided into 4 main groups:

1.Inhibitors of cell wall synthesis of microorganisms:

§ penicillins;

§ cephalosporins;

§ glycopeptides;

§ fosfomycin;

§ carbapenems;

§ bacitracin.

Drugs that destroy the molecular organization and function of cytoplasmic membranes:

§ polymycosins;

§ some antifungal agents.

3. Antibiotics that inhibit protein synthesis:

§ aminoglycosides;

§ macrolides;

§ tetracyclines;

§ group of levomycetin (chloramphenicol);

§ lincosamides (lincosamines).

4. Drugs that disrupt the synthesis of nucleic acids:

§ ansamacrolides (rifamycins);

§ fluoroquinolones;

§ sulfa drugs, trimethoprim, nitromidazoles.

Depending on the interaction of the antibiotic with the microorganism, bactericidal and bacteriostatic antibiotics are isolated.

Chemotherapy is an etiotropic treatment of infectious diseases or malignant tumors, which consists in the selective (selective) suppression of the viability of infectious agents or tumor cells with chemotherapeutic agents. The selectivity of the action of a chemotherapeutic drug lies in the fact that such a drug is toxic to microbes and does not significantly affect the cells of the host organism.

7.1. Antimicrobial chemotherapy drugs

Antimicrobial chemotherapy drugs are drugs that are used to selectively inhibit the growth and reproduction of microbes that cause infectious disease, as well as (rarely and carefully!) For the prevention of infections. There are a number of requirements for chemotherapeutic drugs: ideally, they should have good therapeutic efficacy and minimal toxicity to humans, not cause side effects, have a sufficient spectrum of antimicrobial activity, and inhibit many types of pathogenic microorganisms. They must remain stable over a wide pH range, which makes their oral administration possible, and at the same time have a high percentage of bioavailability (the ability to penetrate into the bloodstream and tissues), have an optimal half-life, and should not cause drug resistance of microorganisms to the drugs used. Current chemotherapy drugs do not fully meet these

requirements. Modern chemotherapy is constantly improving existing drugs and creating new ones. Currently, thousands of chemical compounds with antimicrobial activity are known, but only a few of them are suitable for use as chemotherapeutic agents. Antimicrobial chemotherapeutic agents include the following:

Antibiotics (capable of affecting only cellular forms of microorganisms, antitumor antibiotics are also known);

Synthetic antimicrobial chemotherapeutic drugs of different chemical structure (among them there are drugs that act only on cellular microorganisms or only on viruses).

Antimicrobial chemotherapeutic drugs are usually divided according to the spectrum of their activity. The spectrum of action is determined by which microbes the drug acts on. Among the chemotherapeutic drugs acting on the cellular forms of microorganisms, there are antibacterial, antifungal and antiprotozoal. Antibacterial, in turn, is usually divided into drugs with a narrow and broad spectrum of action. A narrow spectrum has drugs that act against only a small number of varieties of either gram-positive or gram-negative bacteria, a wide spectrum have drugs that affect a fairly large number of species of representatives of both groups of bacteria.

A special group is antiviral chemotherapy drugs (see section 7.6). In addition, there are some antimicrobial chemotherapeutic drugs that also have antitumor activity.

According to the type of action on cellular targets of sensitive microorganisms (morphological structures or individual links of metabolism), microbostatic and microbicidal chemotherapy drugs are distinguished.

Microbicidal antibiotics irreversibly bind and damage cellular targets, causing the death of sensitive microorganisms. Chemotherapy drugs with a static effect inhibit the growth and reproduction of microbial cells, however, when

removal of the antibiotic, the vital activity of pathogens is restored. In the treatment of microbiostatic drugs defensive forces organisms themselves must finally cope with temporarily weakened microorganisms. Depending on the object, the type of action is called bacterio-, fungi-, protozoostatic or, respectively, bacterio-, fungi- and protozoocidal.

7.1.1. Antibiotics

The fact that some microorganisms can somehow retard the growth of others has long been known, but the chemical nature of the antagonism between microbes has long been unclear.

In 1928-1929. A. Fleming discovered a strain of the fungus penicillium (Penicillium notatum), releasing a chemical that inhibits the growth of staphylococcus aureus. The substance was named penicillin, but only in 1940, H. Flory and E. Cheyne were able to obtain a stable preparation of purified penicillin - the first antibiotic that was widely used in the clinic. In 1945, A. Fleming, H. Flory and E. Chain were awarded the Nobel Prize. In our country, a great contribution to the doctrine of antibiotics was made by Z.V. Ermoliev and G.F. Gause.

The term "antibiotic" itself (from the Greek. anti bios- against life) was proposed by S. Waksman in 1942 to refer to natural substances produced by microorganisms and in low concentrations antagonistic to the growth of other bacteria.

Antibiotics - These are chemotherapeutic drugs from chemical compounds of biological origin (natural), as well as their semi-synthetic derivatives and synthetic analogues, which, at low concentrations, have a selective damaging or detrimental effect on microorganisms and tumors.

Classification of antibiotics by chemical structure

Antibiotics have a different chemical structure, and on this basis they are divided into classes. Numerous drugs of antibiotics belonging to the same class have a similar mechanism and mode of action, they are characterized by similar side effects. According to the spectrum of action, while maintaining the patterns characteristic of the class, various drugs, especially of different generations, often have differences.

Main classes of antibiotics:

β-lactams (penicillins, cephalosporins, carbapenems, monobactams);

Glycopeptides;

Lipopeptides;

Aminoglycosides;

Tetracyclines (and glycylcyclines);

macrolides (and azalides);

Lincosamides;

Chloramphenicol / levomycetin;

Rifamycins;

Polypeptides;

Polyenes;

Various antibiotics (fusidic acid, fusafungine, streptogramins, etc.).

Sources of natural and semi-synthetic antibiotics

The main producers of natural antibiotics are microorganisms, which, being in their natural environment(mainly in the soil), synthesize antibiotics as a means of fighting for survival. Plant and animal cells can also produce a variety of chemicals with selective antimicrobial activity (for example, phytoncides, antimicrobial peptides, etc.), but they have not been widely used in medicine as antibiotic producers.

Thus, the main sources of obtaining natural and semi-synthetic antibiotics are:

Mold fungi - synthesize natural β-lactams (fungi of the genus Cephalosporium and penicillium) and fusidic acid;

Actinomycetes (especially streptomycetes) are branching bacteria that synthesize most natural antibiotics (80%);

Typical bacteria, such as bacilli, pseudomonads, produce bacitracin, polymyxins and other substances with antibacterial properties.

Methods for obtaining antibiotics

The main ways to obtain antibiotics:

Biological synthesis (used to obtain natural antibiotics). In the conditions of specialized productions

microbes-producers are cultivated, which secrete antibiotics in the course of their vital activity;

Biosynthesis with subsequent chemical modifications (used to create semi-synthetic antibiotics). First, a natural antibiotic is obtained by biosynthesis, and then its molecule is changed by chemical modifications, for example, certain radicals are attached, as a result of which the antimicrobial and pharmacological properties of the drug are improved;

Chemical synthesis (used to obtain synthetic analogues of natural antibiotics). These are substances that have the same structure as a natural antibiotic, but their molecules are chemically synthesized.

β -Lactams. A class of antibiotics that includes a significant number of natural and semi-synthetic compounds, a characteristic feature of which is the presence of a β-lactam ring, upon destruction of which the drugs lose their activity; penicillins are composed of 5-membered, and cephalosporins 6-membered compounds. Type of action - bactericidal. Antibiotics of this class are divided into penicillins, cephalosporins, carbapenems and monobactams.

Penicillins. Allocate natural (obtained from mushrooms) and semi-synthetic penicillins. Natural remedy - benzylpenicillin(penicillin G) and its salts (potassium and sodium) - active against gram-positive bacteria, but has many disadvantages: it is quickly excreted from the body, destroyed in the acidic environment of the stomach, inactivated by penicillinases - bacterial enzymes that destroy the β-lactam ring. Semi-synthetic penicillins obtained by adding various radicals to the basis of natural penicillin - 6-aminopenicillanic acid - have advantages over natural preparation, including a wide range of activities.

Depot drug(bicillin), acts for about 4 weeks (creates a depot in the muscles), is used to treat syphilis, prevent recurrence of rheumatism and other streptococcal infections, pneumococcal pneumonia. Used to treat meningococcal infections, gonorrhea.

Acid resistant(phenoxymethylpenicillin), for oral administration.

Penicillinase resistant(methicillin, oxacillin), unlike natural penicillin, antibiotics of this group are resistant to the action of penicillinase. Effective against penicillin-resistant staphylococci, as well as against S. pyogenes. Used to treat staphylococcal infections, including abscesses, pneumonia, endocarditis, and septicemia.

Broad Spectrum(ampicillin, amoxicillin). Activity is similar to benzylpenicillin, but active against gram-negative aerobic bacteria: Escherichia coli, Salmonella, Shigella, Haemophilus influenzae.

Antipseudomonal(drugs are divided into 2 groups: carboxypenicillins and ureidopenicillins):

Carboxypenicillins (carbenicillin, ticarcillin, piperocillin). Active against many gram-positive and gram-negative bacteria: Neisseria, most strains of Proteus and other enterobacteria. Of particular importance is the activity against Pseudomonas aeruginosa;

Ureidopenicillins (piperacillin, azlocillin). They are used to treat infections caused by Pseudomonas aeruginosa, the activity against which is 4-8 times higher than that of carbenicillin; and other Gram-negative bacteria, including non-spore-forming anaerobes.

Combined(amoxicillin + clavulanic acid, ampicillin + sulbactam). These drugs include inhibitors enzymes - β -lactamase(clavulanic acid, sulbactam, etc.) containing a β-lactam ring in their molecule. The β-lactam ring, binding to β-lactamases, inhibits them and thus protects the antibiotic molecule from destruction. Enzyme inhibitors act on all microorganisms sensitive to ampicillin, as well as on non-spore-forming anaerobes.

Cephalosporins. One of the most extensive classes of antibiotics. The main structural component of this group of antibiotics is cephalosporin C, structurally similar to penicillin.

General properties of cephalosporins: pronounced bactericidal action, low toxicity, wide therapeutic range

zones, do not affect enterococci, listeria, methicillin-resistant staphylococci, cause cross-allergy with penicillins in 10% of patients. The spectrum of action is wide, but more active against gram-negative bacteria. According to the sequence of introduction, 4 generations (generations) of drugs are distinguished, which differ in their activity spectra, resistance to β-lactamases and some pharmacological properties, therefore drugs of the same generation do not replace drugs of another generation, and supplement:

1 generation(cefamezin, cefazolin, cephalothin, etc.) - active against gram-positive bacteria and enterobacteria. Not active against Pseudomonas aeruginosa. Resistant to staphylococcal β-lactamases, but destroyed by β-lactamases of gram-negative bacteria;

2 generation(cefamandol, cefuroxime, cefaclor, etc.) - in terms of action on gram-positive bacteria, they are equivalent to cephalosporins of the 1st generation, but more active against gram-negative ones, more resistant to β-lactamases;

3rd generation(cefotaxime, ceftazidime, etc.) - have a particularly high activity against gram-negative bacteria from the Enterobacteriaceae family, some are active against Pseudomonas aeruginosa. Less active against gram-positive bacteria. Highly resistant to the action of β-lactamases;

4th generation(cefepime, cefpiron, etc.) - act on some gram-positive bacteria (activity against staphylococci is comparable to cephalosporins of the 2nd generation), high activity against some gram-negative bacteria and Pseudomonas aeruginosa, resistant to the action of β-lactamase.

Monobactams(aztreonam, tazobactam, etc.)- monocyclic β-lactams, narrow spectrum of activity. Very active only against gram-negative bacteria, including Pseudomonas aeruginosa and gram-negative coliform bacteria. Resistant to β-lactamases.

Carbapenems(imipenem, meropenem, etc.) - of all β-lactams have the widest spectrum of action, with the exception of methicillin-resistant strains S. aureus and Enterococcus faecium. Resistant to β-lactamases. Carbapenems- reserve antibiotics,

are prescribed for severe infections caused by multiple resistant strains of microorganisms, as well as for mixed infections.

Glycopeptides(vancomycin and teicoplanin). Active only against gram-positive bacteria, including methicillin-resistant staphylococci. They do not affect gram-negative bacteria due to the fact that glycopeptides are very large molecules that cannot penetrate the pores of gram-negative bacteria. Toxic (ototoxic, nephrotoxic, causes phlebitis).

Used in the treatment of severe infections caused by staphylococci resistant to other antibiotics, especially methicillin-resistant staphylococci, allergy to β-lactams, pseudomembranous colitis caused by Clostridium difficile.

Lipopeptides(daptomycin) - a new group of antibiotics derived from streptomyces, exhibit bactericidal activity, due to the high frequency of side effects, are approved only for the treatment of complicated infections of the skin and soft tissues. They have high activity against gram-positive bacteria, including multiresistant staphylococci and enterococci (resistant to β-lactams and glycopeptides).

Aminoglycosides- compounds, the composition of the molecule of which includes amino sugars. The first drug, streptomycin, was obtained in 1943 by Waksman as a treatment for tuberculosis. Now there are several generations (generations) of drugs: (1) streptomycin, kanamycin, etc.; (2) gentamicin; (3) sisomycin, tobramycin, etc. Aminoglycosides have bactericidal activity, primarily against gram-negative aerobic microorganisms, including Pseudomonas aruginosa, as well as staphylococci, act on some protozoa. Do not act on streptococci and obligate anaerobic microorganisms. Used to treat severe infections caused by enterobacteria and other gram-negative aerobic microorganisms. Nephro- and ototoxic.

Tetracyclines - This is a family of large molecular drugs containing four cyclic compounds. The action type is static. They have a wide spectrum of activity against many gram-positive and gram-negative

A new generation of tetracyclines are semi-synthetic analogues of tetracycline - glycylcyclines, to which the drug belongs tigecycline. Glycylcyclines have a stronger bond with ribosomes. Tigecycline active against a wide range of Gram-positive and Gram-negative bacteria, including multi-resistant, non-fermentative Gram-negative bacteria such as Acinetobacter spp., methicillin-resistant strains of staphylococci, vancomycin-resistant, enterococci, and penicillin-resistant pneumococci. The drug is able to react with bacterial ribosomes that are resistant to the action of natural tetracyclines. Inactive for P. aeruginosa.

Tetracyclines are not used in pediatric practice, as they accumulate in the growing dental tissue ("black teeth syndrome").

Lincosamides(lincomycin and its chlorinated derivative - clindamycin). The spectrum of activity and mechanism of action is similar to macrolides, clindamycin is highly active against obligate anaerobic microorganisms. bacteriostatic effect.

Streptogramins. The natural antibiotic pristinomycin is derived from streptomycetes. The combination of 2 semi-synthetic derivatives of pristinomycin: quinupristin / dalfopristin, in a ratio of 3: 7, has a bactericidal effect against staphylococci and streptococci, including strains resistant to other antibiotics.

1 Gray child syndrome: levomycetin is metabolized in the liver, forming glucuronides, therefore, with a congenital deficiency of the enzyme glucuronyl transferase, the drug accumulates in the blood in toxic concentrations, resulting in grey colour skin, liver enlargement, pain in the heart, swelling, vomiting, general weakness.

Polypeptides(polymyxins). The spectrum of antimicrobial action is narrow (gram-negative bacteria), the type of action is bactericidal. Very toxic. Application - external, currently not used.

Polyena(amphotericin B, nystatin, etc.). Antifungal drugs, the toxicity of which is quite high, therefore, are used more often locally (nystatin), and for systemic mycoses, amphotericin B is the drug of choice.

7.1.2. Synthetic antimicrobial chemotherapy drugs

By chemical synthesis methods, many antimicrobial substances with selective action have been purposefully created, which are not found in wildlife, but are similar to antibiotics in mechanism, type and spectrum of action.

For the first time, a synthetic drug for the treatment of syphilis (salvarsan) was synthesized by P. Ehrlich in 1908 on the basis of organic

arsenic compounds. In 1935, G. Domagk proposed prontosil (red streptocide) for the treatment bacterial infections. The active principle of prontosil was sulfanilamide, which was released during the decomposition of prontosil in the body.

Since then, many varieties of antibacterial, antifungal, antiprotozoal synthetic chemotherapeutic drugs of various chemical structures have been created. Currently, in order to design new synthetic antimicrobial drugs, a constant targeted search is underway in microbes for such proteins that could become new targets that ensure the principle of the selectivity of the action of these drugs.

The most significant groups of widely used synthetic drugs active against cellular forms of microorganisms include sulfonamides, nitroimidazoles, quinolones/fluoroquinolones, oxazolidinones, nitrofurans, imidazoles, and many others (antituberculous, antisyphilitic, antimalarial, etc.).

A special group is made up of synthetic antiviral drugs (see section 7.6).

Sulfonamides. Bacteriostatics have a wide spectrum of activity, including streptococci, Neisseria, Haemophilus influenzae. The basis of the molecule of these drugs is a paraamino group, so they act as analogues and competitive antagonists of para-aminobenzoic acid (PABA), which is necessary for bacteria to synthesize folic (tetrahydrofolic) acid, a precursor of purine and pyrimidine bases. The role of sulfonamides in the treatment of infections in recent times declined as there are many resistant strains, side effects are severe and sulfonamide activity is generally lower than that of antibiotics. The only drug in this group that continues to be widely used in clinical practice is co-trimoxazole and its analogues. Co-trimoxazole (bactrim, biseptol)- a combination drug that consists of sulfamethoxazole and trimethoprim. Trimethoprim blocks the synthesis of folic acid, but at the level of another enzyme. Both components act synergistically, potentiating each other's action. Acts bactericidal. Used for urinary tract infections caused by gram-negative bacteria.

Quinolones/fluoroquinolones(nalidixic acid, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, norfloxacin, etc.) are fluorinated derivatives of 4-quinolone-3 carboxylic acid. In fluoroquinolones, the spectrum is wide, the type of action is cidic. Fluoroquinolones are highly active against the gram-negative spectrum of microorganisms, including enterobacteria, pseudomonads, chlamydia, rickettsia, mycoplasmas. Inactive against streptococci and anaerobes.

Nitroimidazoles(metronidazole, or trichopolum). The type of action is cidal, the spectrum is anaerobic bacteria and protozoa (Trichomonas, Giardia, dysenteric amoeba). Metronidazole is able to be activated by bacterial nitroreductases. Active forms of this drug are able to cleave DNA. Particularly active against anaerobic bacteria, as they are able to activate metronidazole.

Imidazoles(clotrimazole etc.) - antifungal drugs, act at the level of ergosterols of the cytoplasmic membrane.

Nitrofurans(furazolidone and etc.). The type of action is cidal, the spectrum of action is wide. Accumulate in the urine in high concentrations. They are used as uroseptics for the treatment of urinary tract infections.

Oxazolidinones(linezolid). The type of action against staphylococci is static, against some other bacteria (including gram-negative) - cidal, the spectrum of action is wide. It has activity against a wide range of gram-positive bacteria, including methicillin-resistant staphylococci, penicillin-resistant pneumococci, and vancomycin-resistant enterococci. With prolonged use, it can lead to inhibition of hematopoietic functions (thrombocytopenia).

7.2. Mechanisms of action of antimicrobial chemotherapeutic drugs active against cellular forms of microorganisms

The basis for the implementation of the selective action of antimicrobial chemotherapeutic drugs is that the targets for their action in microbial cells differ from those in the cells of the macroorganism. Most chemotherapy drugs interfere with the metabolism of microbial cells, therefore, they are especially active in affecting microorganisms in the phase of their active growth and reproduction.

According to the mechanism of action, the following groups of antimicrobial chemotherapy drugs are distinguished: inhibitors of the synthesis and functions of the bacterial cell wall, inhibitors of protein synthesis in bacteria, inhibitors of the synthesis and functions of nucleic acids that disrupt the synthesis and functions of the CMP (Table 7.1).

Table 7.1. Classification of antimicrobial chemotherapeutic drugs by mechanism of action

7.2.1. Inhibitors of the synthesis and functions of the bacterial cell wall

The most important groups of antimicrobial drugs that selectively act on the synthesis of the bacterial cell wall are β-lactams, glycopeptides and lipopeptides.

Peptidoglycan is the basis of the bacterial cell wall. The synthesis of peptidoglycan precursors begins in the cytoplasm. Then they are transported through the CPM, where they are combined into glycopeptide chains (this stage is inhibited by glycopeptides by binding to D-alanine). The formation of a complete peptidoglycan occurs on the outer surface of the CPM. This stage includes the process of formation of cross-links of heteropolymer chains of peptidoglycan and is carried out with the participation of enzyme proteins (transpeptidases), which are called penicillin-binding proteins (PSBs), since they are the target for penicillin and other β-lactam antibiotics. Inhibition of PBP leads to the accumulation of peptidoglycan precursors in the bacterial cell and the launch of the autolysis system. As a result of the action of autolytic enzymes and an increase in the osmotic pressure of the cytoplasm, the bacterial cell is lysed.

Action lipopeptides is aimed not at the synthesis of peptidoglycan, but at the formation of a channel in the cell wall with the irreversible connection of the hydrophobic part of the lipopeptide molecule with the cell membrane of gram-positive bacteria. The formation of such a channel leads to a rapid depolarization of the cell membrane due to the release of potassium and, possibly, other ions contained in the cytoplasm, resulting in the death of the bacterial cell.

7.2.2. Inhibitors of protein synthesis in bacteria

The target for these drugs is the protein-synthesizing systems of prokaryotes, which differ from eukaryotic ribosomes, which ensures the selectivity of the action of these drugs. Protein synthesis is a multi-step process involving many enzymes and structural subunits. Several target points are known that can be affected by drugs of this group in the process of protein biosynthesis.

Aminoglycosides, tetracyclines and oxazolidinones bind to the 30S subunit, blocking the process even before the start of protein synthesis. Aminoglycosides bind irreversibly to the 30S subunit of ribosomes and disrupt the attachment of tRNA to the ribosome, the formation of defective initial complexes occurs. Tetracyclines bind reversibly to the 30S subunit of ribosomes and prevent the attachment of a new tRNA aminoacyl to the acceptor site and the movement of tRNA from the acceptor to the donor site. Oxazolidinones block the binding of two ribosome subunits into a single 70S complex, disrupt the termination and release of the peptide chain.

Macrolides, chloramphenicol, lincosamides and streptogramins bind to the 50S subunit and inhibit the process of polypeptide chain elongation during protein synthesis. Chloramphenicol and lincosamides disrupt the formation of a peptide catalyzed by peptidyl transferase, macrolides inhibit the translocation of peptidyl tRNA. However, the effect of these drugs is bacteriostatic. Streptoramines, quinupristin/dalfopristin inhibit protein synthesis in a synergistic manner, exerting a bactericidal effect. Quinupristin binds the 50S subunit and prevents polypeptide elongation. Dalfopristin joins nearby, changes the conformation of the 50S-ribosomal subunit, thereby increasing the strength of quinupristin binding to it.

7.2.3. Nucleic acid synthesis and function inhibitors

Several classes of antimicrobials are capable of disrupting the synthesis and function of bacterial nucleic acids, which is achieved in three ways: inhibition of the synthesis of precursors of purine pyrimidine bases (sulfonamides, trimethoprim), suppression of DNA replication and functions (quinolones/fluoroquinolones, nitroimidazoles, nitrofurans) and inhibition of RNA polymerase (rifamycins). For the most part, this group includes synthetic drugs; among antibiotics, only antibiotics have a similar mechanism of action. rifamycins, which bind to RNA polymerase and block mRNA synthesis.

Action fluoroquinolones associated with inhibition of bacterial DNA synthesis by blocking the enzyme DNA gyrase. DNA gyrase is an ΙΙ topoisomerase that provides the unwinding of the DNA molecule necessary for its replication.

Sulfonamides- structural analogues of PABA - can competitively bind and inhibit the enzyme that is needed to convert PABA to folic acid - a precursor of purine and pyrimidine bases. These bases are essential for the synthesis of nucleic acids.

7.2.4. Inhibitors of synthesis and functions of the CPM

The number of antibiotics that specifically act on bacterial membranes is small. The best known are polymyxins (polypeptides), to which only gram-negative bacteria are sensitive. Polymyxins lyse cells, damaging the phospholipids of cell membranes. Due to toxicity, they are used only for the treatment of local processes and are not administered parenterally. Currently not used in practice.

Antifungal drugs (antimycotics) damage the ergosterols of the CPM of fungi (polyene antibiotics) and inhibit one of the key enzymes in the biosynthesis of ergosterols (imidazoles).

7.2.5. Side effects on microorganisms

The use of antimicrobial chemotherapy drugs not only has a direct inhibitory or detrimental effect on microbes, but can also lead to the formation of atypical forms of microbes (for example, the formation of L-forms of bacteria) and persistent forms of microbes. The widespread use of antimicrobial drugs also leads to the formation of antibiotic dependence (rarely) and drug resistance - antibiotic resistance (quite often).

7.3. Drug resistance of bacteria

In recent years, the frequency of isolation of microbial strains resistant to antibiotics has increased significantly.

Antibiotic resistance is the resistance of microbes to antimicrobial chemotherapy drugs. Bacteria should be considered resistant if they are not neutralized by such drug concentrations that are actually created in the macroorganism. Antibiotic resistance can be natural or acquired.

7.3.1. Natural sustainability

Natural stability is an innate specific feature of a microorganism. It is associated with the lack of a target for a particular antibiotic or its unavailability. In this case, the use of this antibiotic for therapeutic purposes is impractical. Some types of microbes are initially resistant to certain families of antibiotics, either as a result of the lack of an appropriate target, for example, mycoplasmas do not have a cell wall, therefore they are insensitive to all drugs acting at this level, or as a result of bacterial impermeability for a given drug, for example, gram-negative microbes are less permeable to large molecular weight compounds than Gram-positive bacteria because their outer membrane has narrow pores.

7.3.2. Acquired resistance

Acquired resistance is characterized by the ability of individual strains of microorganisms to survive at concentrations of antibiotics that can inhibit the bulk of the microbial population of a given species. With further spread of antibiotic-resistant strains, they may become predominant.

Since the 40s of the XX century, when antibiotics began to be introduced into medical practice, bacteria began to adapt extremely quickly, gradually forming resistance to all new drugs. The acquisition of resistance is a biological pattern associated with the adaptation of microorganisms to environmental conditions. Not only bacteria can adapt to chemotherapy drugs, but also other microbes - from eukaryotic forms (protozoa, fungi) to viruses. The problem of the formation and spread of drug resistance in microbes is especially significant for nosocomial infections caused by the so-called hospital strains, which, as a rule, have multiple resistance to different groups of antimicrobial chemotherapeutic drugs (the so-called polyresistance).

7.3.3. Genetic Basis of Acquired Resistance

Antimicrobial resistance is determined and maintained by resistance genes and

conditions conducive to their spread in microbial populations. These genes can be localized both in the bacterial chromosome and in plasmids, and can also be part of prophages and mobile genetic elements (transposons). Transposons carry out the transfer of genes that cause resistance from the chromosome to plasmids and vice versa, as well as the transfer between plasmids and bacteriophages.

The emergence and spread of acquired resistance to antimicrobial drugs is provided by genotypic variability, associated primarily with mutations. Mutations occur in the microbial genome regardless of the use of the antibiotic, i.e. the drug itself does not affect the frequency of mutations and is not their cause, but serves as a selection factor, since in the presence of an antibiotic, resistant individuals are selected, while sensitive ones die. Further, resistant cells give birth and can be transferred to the body of the next host (human or animal), forming and spreading resistant strains. The existence of the so-called co-selection is also assumed, i.e. selective pressure not only antibiotics, but also other factors.

Thus, acquired drug resistance can arise and spread in a bacterial population as a result of:

Mutations in the genome of a bacterial cell with subsequent selection (i.e. selection) of mutants, such selection is especially active in the presence of antibiotics;

Transfer of transmissible resistance plasmids (R-plasmids). However, some plasmids can be transferred between bacteria. different types, therefore, the same resistance genes can be found in bacteria that are taxonomically distant from each other (for example, the same plasmid can be in gram-negative bacteria, in penicillin-resistant gonococcus, and in ampicillin-resistant Haemophilus influenzae);

Transfer of transposons carrying resistance genes. Transposons can migrate from a chromosome to a plasmid and vice versa, as well as from a plasmid to another plasmid. Thus, further resistance genes can be transferred to daughter cells or by transferring plasmids to other recipient bacteria;

Expression of gene cassettes by integrons. Integrons are genetic elements that contain an integrase gene, a specific integration site and a promoter next to it, which gives them the ability to integrate mobile gene cassettes (for example, containing resistance genes) and express the promoterless genes present in them.

7.3.4. Implementation of Acquired Resilience

To carry out its antimicrobial action, the drug must, while remaining active, pass through the membranes of the microbial cell and then bind to intracellular targets. However, as a result of the acquisition of resistance genes by the microorganism, some properties of the bacterial cell are changed in such a way that the action of the drug cannot be performed.

Most often, stability is implemented in the following ways:

There is a change in the structure of targets that are sensitive to the action of antibiotics (target modification). The target enzyme can be altered so that its function is not impaired, but the ability to bind to the chemotherapy drug (affinity) is drastically reduced, or a metabolic bypass can be turned on, i.e. another enzyme is activated in the cell, which is not affected by this drug. For example, a change in the structure of PBP (transpeptidase) leads to resistance to β-lactams, a change in the structure of ribosomes to aminoglycosides and macrolides, a change in the structure of DNA gyrases to fluoroquinolones, and RNA synthetase to rifampicin.

The target becomes inaccessible due to a decrease in the permeability of cell membranes or an efflux mechanism - a system of active energy-dependent release of an antibiotic from cell membranes, which most often manifests itself when exposed to small doses of the drug (for example, the synthesis of specific proteins in the outer membrane of the bacterial cell wall can provide free release of tetracycline from cells to the environment).

The ability to inactivate the drug by bacterial enzymes is acquired (enzymatic inactivation of antibiotics). Some bacteria are able to produce specific

enzymes that cause resistance. Such enzymes can degrade the active site of an antibiotic, for example, β-lactamases degrade β-lactam antibiotics to form inactive compounds. Or enzymes can modify antibacterial drugs by adding new chemical groups, which leads to the loss of antibiotic activity - aminoglycoside adenyl transferase, chloramphenicol acetyl transferase, etc. (thus, aminoglycosides, macrolides, lincosamides are inactivated). The genes encoding these enzymes are widely distributed among bacteria and are more often found in plasmids, transposons, and gene cassettes. To combat the inactivating effect of β-lactamases, inhibitor substances are used (for example, clavulanic acid, sulbactam, tazobactam).

It is almost impossible to prevent the development of antibiotic resistance in bacteria, but it is necessary to use antimicrobials in such a way as to reduce the selective effect of antibiotics, which contributes to the stability of the genome of resistant strains and does not contribute to the development and spread of resistance.

The implementation of a number of recommendations contributes to curbing the spread of antibiotic resistance.

Before prescribing the drug, it is necessary to establish the causative agent of the infection and determine its sensitivity to antimicrobial chemotherapeutic drugs (antibiogram). Taking into account the results of the antibiogram, the patient is prescribed a narrow-spectrum drug with the greatest activity against a specific pathogen, at a dose 2-3 times higher than the minimum inhibitory concentration. Since it is necessary to start treatment of the infection as early as possible, while the pathogen is unknown, broader spectrum drugs are usually prescribed that are active against all possible microbes that most often cause this pathology. Correction of treatment is carried out taking into account the results of bacteriological examination and determination of the individual sensitivity of a particular pathogen (usually after 2-3 days). Doses of drugs should be sufficient to provide microbostatic or microbicidal concentrations in biological fluids and tissues.

It is necessary to present the optimal duration of treatment, since clinical improvement is not a reason to discontinue the drug, because pathogens may persist in the body and there may be a relapse of the disease. Minimize the use of antibiotics to prevent infectious diseases; during treatment, after 10-15 days of antibiotic therapy, change antimicrobial drugs, especially within the same hospital; in severe, life-threatening infections, treat simultaneously with 2-3 combined antibiotics with a different molecular mechanism of action; use antibiotics combined with β-lactamase inhibitors; pay special attention to the rational use of antibiotics in such areas as cosmetology, dentistry, veterinary medicine, animal husbandry, etc.; do not use in veterinary medicine antibiotics used to treat humans.

Recently, however, even these measures have become less effective due to the diversity of genetic mechanisms of resistance formation.

A very important condition for right choice antimicrobial drug in the treatment of a particular patient are the results of special tests to determine the sensitivity of the infectious agent to antibiotics.

7.4. Determination of bacterial susceptibility to antibiotics

To determine the sensitivity of bacteria to antibiotics (antibiogram) is usually used:

Agar Diffusion Methods. The studied pure culture of the microbe is inoculated onto the agar nutrient medium, and then antibiotics are added. Usually, drugs are applied either to special wells in agar (quantitative method), or discs with antibiotics are laid out on the surface of the seed (disc method is a qualitative method). The results are taken into account in a day by the presence or absence of microbial growth around the holes (discs);

Methods for determining minimum inhibitory (MIC) and bactericidal (MBC) concentrations, i.e. the minimum level of antibiotic that allows in vitro prevent visible microbial growth in the culture medium or completely sterilize it. These are quantitative methods that allow

It is necessary to calculate the dose of the drug, since during treatment, the concentration of the antibiotic in the blood should be significantly higher than the MIC for the infectious agent. The introduction of adequate doses of the drug is necessary for effective treatment and prevention of the formation of resistant microbes. There are accelerated methods using automatic analyzers.

Molecular genetic methods (PCR, etc.) make it possible to study the microbial genome and detect resistance genes in it.

7.5. Complications of antimicrobial chemotherapy on the part of the macroorganism

Like any drug, almost every group of antimicrobial chemotherapy drugs can have side effect on the macroorganism and other drugs used in a particular patient.

The most common complications of antimicrobial chemotherapy include:

Dysbiosis (dysbacteriosis). The formation of dysbiosis leads to dysfunction of the gastrointestinal tract, the development of beriberi, the addition of a secondary infection (candidiasis, pseudomembranous colitis caused by C. difficile, etc.). The prevention of these complications consists in prescribing, if possible, drugs with a narrow spectrum of action, combining the treatment of the underlying disease with antifungal therapy (nystatin), vitamin therapy, the use of eubiotics (pre-, pro- and synbiotics), etc .;

Negative impact on immune system. The most common are allergic reactions. Hypersensitivity can occur both to the drug itself and to its decay products, as well as to the complex of the drug with whey proteins. Allergic reactions develop in about 10% of cases and manifest as rash, itching, urticaria, Quincke's edema. Relatively rare is such a severe form of hypersensitivity as anaphylactic shock. This complication can be caused by β-lactams (penicillins), rifamycins, etc. Sulfonamides can cause delayed-type hypersensitivity. Complicated warning

niya consists in a careful collection of an allergic history and the appointment of drugs in accordance with the individual sensitivity of the patient. It is also known that antibiotics have some immunosuppressive properties and can contribute to the development of secondary immunodeficiency and the weakening of immunity. The toxic effect of drugs is more often manifested with prolonged and systematic use of antimicrobial chemotherapeutic drugs, when conditions are created for their accumulation in the body. Especially often such complications occur when the target of the drug action are processes or structures that are similar in composition or structure to similar structures of macroorganism cells. Children, pregnant women, patients with impaired liver and kidney function are especially susceptible to the toxic effect of antimicrobial drugs. Adverse toxic effects can manifest as neurotoxic (glycopeptides and aminoglycosides have an ototoxic effect up to complete hearing loss due to effects on the auditory nerve); nephrotoxic (polyenes, polypeptides, aminoglycosides, macrolides, glycopeptides, sulfonamides); general toxic (antifungal drugs - polyenes, imidazoles); oppression of hematopoiesis (tetracyclines, sulfonamides, levomycetin / chloramphenicol, which contains nitrobenzene - a suppressor of bone marrow function); teratogenic (aminoglycosides, tetracyclines interfere with the development of bones, cartilage in the fetus and children, the formation of tooth enamel - brown coloration of the teeth, levomycetin / chloramphenicol is toxic to newborns in which liver enzymes are not fully formed ("gray baby" syndrome), quinolones - act on developing cartilage and connective tissue).

Prevention of complications consists in refusing drugs that are contraindicated for this patient, monitoring the state of the functions of the liver, kidneys, etc.

Endotoxic shock (therapeutic) occurs in the treatment of infections caused by Gram-negative bacteria. Administration of antibiotics causes cell death and destruction and the release of large amounts of endotoxin. This is a natural phenomenon, which is accompanied by a temporary deterioration in the clinical condition of the patient.

Interaction with other drugs. Antibiotics can help potentiate the action or inactivate other drugs (for example, erythromycin stimulates the production of liver enzymes, which begin to rapidly metabolize drugs for various purposes).

7.6. Antiviral chemotherapy drugs

Antiviral chemotherapy drugs are etiotropic drugs that can affect individual parts of the reproduction of certain viruses, disrupting their reproduction in infected cells. Some drugs have virucidal properties.

Nucleoside analogues, synthetic peptides, analogues of pyrophosphate, thiosemicabazones, synthetic amines are used as antiviral chemotherapy drugs.

According to the mechanism of action, antiviral chemotherapy drugs are divided into drugs that disrupt the penetration of the virus into the cell and its deproteinization, inhibitors of the synthesis of viral nucleic acids, and inhibitors of viral enzymes.

To drugs that inhibit the process of penetration of the virus into the cell and its deproteinization, relate:

Synthetic amines (amantanine), which specifically inhibits type A influenza viruses, disrupting the process of "undressing" the virus, interacting with the matrix protein;

Artificially synthesized peptides, in particular the 36 amino acid peptide (enfuvirtide), which inhibits the process of cell membrane fusion and HIV-1 by changing the conformation of the transmembrane protein gp41 (see section 17.1.11).

Drugs that inhibit the process of replication of viral nucleic acids. Inhibitors of the synthesis of viral nucleic acids in most cases are analogues of nucleosides. Some of them (iodoxyuridine) can act as antimetabolites, integrating into the viral nucleic acid during its replication and thus terminating further chain elongation. Other drugs act as viral polymerase inhibitors.

Viral polymerase inhibitors are active in the phosphorylated form. Since inhibitors of viral polymerases can

also inhibit cellular polymerases, preference is given to those drugs that specifically inhibit viral enzymes. The drugs that selectively act on viral polymerase include the guanosine analogue acyclovir. Phosphorylation of acyclovir is most effectively carried out not by cellular kinase, but by viral thymidine kinase, which is present in herpes simplex viruses type I and II, against which this drug is active.

The thymidine analog vidarabine is also an inhibitor of viral polymerases.

Non-nucleoside derivatives can also inhibit viral polymerases, in particular, the organic analogue of the inorganic pyrophosphate foscarnet, which, by binding the polyphosphate groups of the DNA polymerase of the virus, blocks the elongation of the DNA molecule. Active against hepatitis B viruses, cytomegaloviruses, HIV-1.

Reverse transcriptase inhibitory drugs are discussed in section 17.1.11.

Drugs that inhibit the formation of new virions

1. A derivative of thiosemicarbisones (metisazon) blocks the late stages of viral replication, causing the formation of unformed, non-infectious viral particles. Active against variola virus.

2. Viral enzyme inhibitors. These include synthetic peptides, which, penetrating into the active center of the enzyme, suppress its activity. This group of drugs includes the inhibitor of viral neuraminidase of influenza A and B viruses oseltamivir. As a result of the action of neuraminidase inhibitors, new virions do not bud out of the cell.

The development of retroviruses, in particular HIV, includes the cleavage of a polypeptide formed during the translation of viral mRNA into functionally active fragments by a viral protease. Protease inhibition leads to the formation of non-infectious virions. Retroviral protease inhibitors are drugs ritonavir, indinavir.

To virucidal drugs, which inactivate extracellular virions include: oxalin, effective against influenza viruses, herpes; alpizarin and a number of others.

Tasks for self-training (self-control)

A. Antibiotics may act on:

1. Bacteria.

2. Viruses.

4. The simplest.

5. Prions.

B. Specify the main groups of antibiotics that disrupt cell wall synthesis:

1. Tetracyclines.

2. β-Lactams.

3. Lincosamines.

4. Glycopeptides.

5. Polyenes.

b. Specify the groups of synthetic microbial preparations:

1. Polyenes.

2. Sulfonamides.

3. Imidazoles.

4. Quinolones.

5. Aminoglycosides.

G. Specify the groups of antimicrobial drugs that disrupt protein biosynthesis:

1. Oxazolidinones.

2. Tetracyclines.

3. Aminoglycosides.

4. Fluoroquinolones.

5. Carbopinems.

D. Complications from the microorganism:

1. Dysbiosis.

2. Endotoxic shock.

3. Anaphylactic shock.

4. Violation of hematopoiesis.

5. Toxic effect on the auditory nerve.

E. In medical practice, for the treatment of infectious processes, combined preparations are used, consisting of a combination of amoxicillin + clavulanic acid and ampicillin + sumbactam. Explain their advantage over individual antibiotics.