TETRACYCLINES — group of the antibiotics which are characterized by a community of a chemical structure (a four-membered naftatsenovy kernel), a wide range and the similar mechanism of antibacterial action.
Distinguish natural (biosynthetic) and semi-synthetic T. Natural T. receive as a result of biosynthesis, semi-synthetic — by chemical transformation of natural T. K to natural T. belong chlortetracyclin (see), Oxytetracyclinum (see), tetracycline, demetilkhlortetratsiklin; to semi-synthetic — metacycline (a synonym Rondomycinum), doxycycline (a synonym Vibramycinum), Morphocyclinum (a synonym morfolinometiltetratsiklin), ditetracycline, and also drugs produced abroad — minocycline, pyrrolidinomethyltetracycline (a synonym Reverinum), lizinometiltetratsiklin N other.
The first of T. the chlortetracyclin (1948) formed at biosynthesis of Streptomyces aureofaciens and Oxytetracyclinum (1950) produced by Streptomyces rimosus were discovered. Tetracycline was received at first as a result of recovery dehalogenation of chlortetracyclin, and then, after allocation of highly active strains of producers (representatives of the sort Streptomyces) — by biosynthesis. Natural and semi-synthetic T. are similar among themselves on the main properties and use. Tetracycline — the most eurysynusic antibiotic of this group in medicine, chlortetracyclin in medical practice do not apply; Oxytetracyclinum is used by hl. obr. for receiving semi-synthetic derivatives — metacycline and doxycycline.
T. — crystal powders of yellow color; in the form of the basis badly rastvorima in water; various salts. hl. obr. hydrochlorides, are dissolved better. The smallest lipophilicity Oxytetracyclinum, average — tetracycline, high — metacycline and doxycycline possesses that defines their different absorbability at intake.
Distinctions in a range of antimicrobic action of separate T. are insignificant and have no practical value. T. are more active in acid medium; pona of two - and trivalent metals, homogenates of bodies and fabrics reduce their activity. T. communicate serum proteins (22 — 25% of the entered dose), however this communication is reversible. T. work on out of - and intracellularly located microorganisms.
T. — drugs of bacteriostatic type of action. They inhibit synthesis of protein (contact 30 S-subunits of ribosomes of bacterial cells, breaking broadcast of genetic information) in bacterial cells and suppress effect of the enzymes catalyzing binding aminoacyl - acceptor RNA with acceptors of ribosomes. T. break permeability of a microbic cell. They form complexes with bivalent cations of metals. Resistance of gram-negative bacteria to T. it is more often caused by extra chromosomal factors — R-plasmids (see. Plasmids ), bearing genes of medicinal stability and transferred among activators by conjugation (see. Conjugation at bacteria ). Resistance to T. usually is followed by resistance to other antibiotics of a broad spectrum of activity.
T. — antibiotics of a broad spectrum of activity (tab). They are highly active in vitro concerning many gram-positive and gram-negative bacteria, spirochetes, leptospir, rickettsiae, chlamydias, nek-ry protozoa, a maloaktivna or are not active in the relation a protea, pseudo-monads, the majority of fungi and viruses. Stafilokokki, including anaerobic, are sensitive to 1 mkg/ml of an antibiotic less; activators of a malignant anthrax, gas gangrene, diphtheria, an actinomycosis — to 0.3 — 1,5 mkg/ml. Growth of the majority sensitive to T. enterobakteriya (escherichias, an enterobakter, klebsiyell, salmonellas, shigellas) is suppressed at concentration with 1 — 25 mkg/ml. In concentration of 0,5 — 5 mkg/ml tetracyclines suppress the majority of strains of neysseriya though sensitivity to their operation of the causative agent of gonorrhea differs in variability. Sensitive and resistant strains occur among asporous gram-negative anaerobe bacterias (bacteroids). Sometimes T. are inefficient at inf. the diseases caused by activators, naira, salmonellas, in vitro, sensitive to them.
Use of tetracyclines in clinic
T. apply at the diseases caused by activators, sensitive to them — quinsy, bronchitis, pleurisy, pneumonia, a septic endocarditis, cholecystitis, bacterial and amoebic dysentery, whooping cough, gonorrhea, sypny and a typhinia, trachoma, a psittacosis, infections of urinary tract. T. are effective at treatment of an acute and chronic brucellosis (in a combination to streptomycin), tularemias, a malignant anthrax, at prevention and treatment of cholera, the diseases caused by mycoplasmas. T. in combination with antibiotics of group of aminoglycosides appoint at the treatment of endotoxic shock and bacteremia caused by gram-negative microorganisms. T. can be effective at treatment of the diseases caused by the microorganisms steady against benzylpenicillin and streptomycin.
Due to the wide spread occurance of tetratsiklinoustoychivy strains of microorganisms, bacteriostatic type of action of T., rather high frequency of side reactions and implementation in practice of new antibiotics a wedge, use of natural T. it is limited. They are appointed generally at respiratory infections, urinary tract, and also in cases of hypersensitivity of patients to other antibiotics. At treatment of diseases of urinary tract preliminary studying of sensitivity of activators to tetracyclines is obligatory.
T. appoint inside, and also enter intramusculary, intravenously, into cavities. T. are well soaked up at use inside (especially at reception on an empty stomach): at a dose of 0,5 — 1 g the maximum concentration in blood (1,5 — 3,5 mkg/ml) find them in 2 — 3 hours after reception. Therapeutic concentration in blood are observed at reception of T. inside in a dose of 0,25 — 0,5 g every 6 — 8 hour. Color of T. it is not soaked up and allocated through went. - kish. path.
At intramuscular introduction of T. there is fuller absorption and accumulation of antibiotics in blood in high concentration therefore they are entered in smaller doses. T. badly get through a blood-brain barrier and are found in cerebrospinal liquid in the concentration making 5 — 10% from observed in blood. Concentration of T. in cerebrospinal liquid raises at inflammatory diseases of a brain and its covers; at long intravenous administration can reach 5 mkg/ml and more. Therapeutic concentration of T. are created in ascitic liquid, exudate of pleural and synovial cavities. T. get through a placenta and into breast milk. In significant amounts of T. collect in a liver, kidneys, a spleen, lungs, in a bone tissue, especially proliferating, in dentine and enamel of milk teeth. Maintenance of T. in bile by 5 — 10 times exceeds concentration in blood. T. are brought out of an organism of hl. obr. kidneys by glomerular filtering and through went. - kish. path. With urine 10 — 25% of the antibiotic accepted inside and 20 — 70% entered intravenously are removed. On average through went. - kish. the path is removed by 20 — 50% of the accepted dose. At disturbance of secretory function of kidneys excretion of tetracyclines decreases, and their concentration in blood increases.
Tetracycline in tablets or capsules is accepted inside on an empty stomach, by 3 — 4 times a day. For adults a single dose of 0,25 g, the highest daily dose of 2 g. To children up to 8 years of T. do not appoint; the daily dose for children is more senior than 8 years of 20 — 25 mg/kg. Duration of a course of treatment is 5 — 10 days and more; after 4 — a 7-day break repeated courses are possible. Forms of production of tetracycline (the basis or a hydrochloride) for intake: the tablets and capsules containing 0,05; 0,1 and 0,25 g of an antibiotic. For the prevention of candidiasis release tablets of drug with nystatin.
Tetracycline the hydrochloride for intramuscular introduction (it is possible to enter also into cavities) is appointed at impossibility of a pla difficulty of intake, and also at a severe disease. A single dose for adult 0,05 — 0,1 g; for children of 8 — 10 years 0,05 g, 10 — 14 years 0,06 g. The drug is administered by 2 — 3 times a day with 1 — 2% solution of novocaine. Form of release: sterile powder in bottles on 0,1 g.
The oculentum of tetracycline contains 10 mg of tetracycline of the basis in 1 g of a basis; it is appointed by 3 — 5 times a day at treatment of conjunctivitis, a blepharitis, keratitis, helcomas, trachoma and other diseases of the eyes caused by activators, sensitive to tetracycline.
Skin ointment of tetracycline contains 30 mg of tetracycline of the basis in 1 g of a basis; it is used at treatment of the diseases of skin (acneform rash, a staphyloderma, folliculites, trophic ulcers, etc.) caused by activators, sensitive to tetracycline.
Ditetracycline eye maz contains 1,5 mg of ditetracycline (N, N '-dibenziletilendiamino - dimethylditetracycline) the prolonged action in 1 g of a basis. Locally at single use provides therapeutic concentration, edges remains within 48 — 72 hour.
Morphocyclinum (N - morfolinometiltetratsiklin) — karboksamidny derivative tetracycline for intravenous administration. Morphocyclinum is appointed at the heavy course of the diseases caused sensitive to T. activators. Morphocyclinum is entered 1 — 2 time a day in a dose of 0,1 — 0,15 g in the form of 1,25 — 2,5% of the solution prepared just before introduction for 5% solution of glucose. Form of release: sterile powder in bottles on 0,1 and 0,15 g.
Oletetrinum (Tetraolenum, Sigmamycinum) — the combined dosage form of tetracycline of the basis and Oleandomycinum of phosphate in the ratio 2:1. Drug possesses more broad spectrum of activity in comparison with other T. Indications and contraindications to purpose of Oletetrinum, dose, form of release — see. Oletetrinum .
Metacycline — semi-synthetic derivative Oxytetracyclinum. On a range and the mechanism of antibacterial action it is similar to tetracycline. The main feature of metacycline is good absorbability at intake and long preservation of therapeutic concentration in blood (during 12 hours). After intake in a dose of 0,15 g the maximum concentration in blood are created in 2 — 3 hours. It well gets into fabrics and liquids of an organism. At moderately severe diseases the daily dose for adults makes 0,6 g, at a heavy current it can be doubled; drug is used by 2 — 3 times a day. To children 8 years metacycline are more senior appoint at the rate of 7,5 — 10 mg/kg 2 — 3 times a day. Form of release: capsules on 0,15 and 0,3 g.
Doxycycline — semi-synthetic derivative Oxytetracyclinum. On a range and the mechanism of antibacterial action it is close to other T.; concerning stafilokokk, streptococci, enterococci in some cases exceeds other T in a degree of activity. Important advantages of doxycycline are its best absorbability at intake in comparison with tetracycline and metacycline, the prolonged action, the best penetration through fabric barriers. Indications to purpose of doxycycline same, as at use of other T., however the effect is reached during the use of much lower doses and 1 — 2-times introduction in day. For adults the daily dose makes 0,1 g once a day (an initial dose of 0,1 g 2 times a day). At heavy disease the drug is administered on 0,1 g by 2 times a day. To children 8 years drug are more senior appoint at the rate of 5 mg/kg in the first days and 2 mg/kg in the subsequent. Duration of a course 7 — 10 days. Administration of drug during food reduces possible irritant action. Form of release: capsules on 0,05 and 0,1 g.
Side effect is observed very often (to 30% of cases of use of T.). Tetracycline and doxycycline are least toxic, Oxytetracyclinum is intermediate. Toxic action of T. it is more often observed at intravenous administration of drugs in high doses. At normal function of kidneys and a liver the toxic phenomena have reversible character. In cases of disturbance secretory faugh and ktsp and kidneys and a nephropathy of pregnant women perhaps heavy hepatotoxic action, up to fatty dystrophy of a liver. At peroral introduction disturbances from outside are observed went. - ksh. a path — it is lowered appetite, nausea, vomiting, a meteorism, a diarrhea (to 15% of cases). The dispeptic phenomena can be connected with direct irritant action of T. on a wall of intestines or are caused by dysbacteriosis. To manifestations of irritant action of T. ulcer or vesicular stomatitis belongs (see). In some cases after 4 — 7 days of treatment of T. the anorectal or genitorektalny syndrome develops (colitis, a proctitis, prurit, a vulvovaginitis, etc.). Allergic reactions are observed in 4% of cases and shown by skin rashes, dermatitis, damage of mucous membranes (see the Allergy). Frequency of emergence of photodermatoses depends on a dose of an antibiotic and intensity of insolation. At reception of T. disturbance of normal microflora is possible, at the same time at the weakened patients with a serious illness the superinfections caused steady against T develop. strains of microorganisms (staphylococcus, proteas, fungi of the sort Candida, etc.).
Ability of T. it is especially dangerous to collect in a bone tissue at their appointment to pregnant women (accumulation in a bone skeleton of a fruit can be followed by delay of growth of bones). Accumulation of T. in dentine and enamel of a milk tooth leads to their darkening, a hypoplasia of enamel, increase in frequency of caries (makes up to 20% of cases of use of T. and seldom arises at purpose of doxycycline). Action of T is possible. on a hemopoiesis. Heavy side reactions (Fankoni's syndrome) can develop under the influence of decomposition products T., especially at persons with a renal failure (see. Fankoni nefronoftiz ).
Table. ANTIMIKROVNY RANGE of TETRACYCLINES
Bibliography: Navashin S. M. and Fomina I. Ratsionalnaya antibioti-koterapnya, M., 1982.
S. M. Navashin, I. Fomina.