STREPTOMYCIN — the antibiotics of group of aminoglycosides produced by actinomycetes of types of Streptomyces.
The first of antibiotics of this group — streptomycin was allocated by S. Ya. Vaksman and sotr. at the end of 1943. In 1946 by catalytic recovery of streptomycin dihydrostreptomycin was received. Further it was established that dihydrostreptomycin is formed by actinomycetes of a type of Str. humidus. Total formula of streptomycin of sulfate (C 21 H 39 O 12 N 7 ) 2 - 3H 2 SO 4 , molecular weight (weight) 728,7. Total formula of dihydrostreptomycin of sulfate (C 21 H 41 N 7 O 12 ) 2 • 3H 2 SO 4 , molecular weight 730,7.
Streptomycin — organic base, a molecule to-rogo consists of three glycosides: a streptidin (aminotsiklitol), Streptasums and a N-methyl-L-glycosamine (two last make streptobiozamin). In a molecule of streptomycin streptobiozamin it is connected through oxygen atom with the 4th carbon atom of a streptidin. The molecule of a streptidin includes two basic guaninovy groups defining ototoxicity of an antibiotic, and a methylglycosamine — metilenaminny group.
Digidrostreptomitsin differs from streptomycin in absence of aldehydic group, edges will be transformed in oxymethyl at recovery of streptomycin. Both antibiotics easily form salts.
In medical practice apply streptomycin sulfate, a streptosulmitsin sulfate (sodium bisulfite derivative streptomycin), a calcium chloride complex of streptomycin (binary salt of Calcii chloridum and streptomycin of a hydrochloride), etc. Digidrostreptomitsin most often use in the form of p-aminosalicylic salt — Pasomycinum.
Streptomycin and dihydrostreptomycin well, in solutions of novocaine, are much less than rastvorima in water in organic solvents. Solutions of streptomycin and dihydrostreptomycin keep activity at pH 4,0 — 7,0 and t ° 28 ° within 2 months, and at t ° 4 ° — over 3 months.
Streptomycin and dihydrostreptomycin possess a wide range of antibacterial action (tab). In concentration less than 10 mkg/ml these antibiotics suppress growth of the majority of strains of Brucella, Mycobacterium, Yersinia, Escherichia, Proteus, Salmonella, Shigella, Haemophilus, Staphylococcus, etc.; Klebsiella pneumoniae is highly sensitive to them, representatives of Corynebacte-rium, Enterobacter, Streptococcus, etc. are less sensitive. Suppression of growth of the majority of strains of these microorganisms is observed at concentration of 10 — 100 mkg/ml. Separate strains, sensitive to S., occur among representatives of the sort Pseudomonas, but in general most of representatives of this sort are steady against their action. Pages are inactive concerning anaerobe bacterias, fungi, protozoa, rickettsiae and viruses. Strains of microorganisms, for to-rykh value of the minimum overwhelming concentration of S. exceed 15 mkg/ml, are regarded as steady.
Unlike penicillin (see) streptomycin are active in the relation not only the breeding microbes but also being in a lag phase possess bactericidal action, suppress reproduction only vnekletochno of the located activators. A serious problem is bystry emergence of streptomitsinoustoychivy strains of bacteria (at quickly breeding microbes stability can arise within several days). Streptomycin resistance is followed by full cross dihydrostreptomycin resistance (see. Medicinal stability of microorganisms ).
At treatment of tuberculosis streptomycin resistance develops more slowly owing to the long period of generation of mycobacteria, is frequent several weeks later after an initiation of treatment. Patients * treated only streptomycin, within 100 — 120 days have antibiotic-resistant 70 — 80% of the allocated mycobacteria. The wide spread occurance of steady bacteria is connected with selection of initially resistant strains which are gradually forcing out individuals, sensitive to an antibiotic. Streptomycin resistance is caused by an inactivation of an antibiotic the specific enzymes (adeniliruyushchy or phosphorylating streptomycin) produced by steady cells (formation of these enzymes is determined by plasmid genes); suppression of binding of an antibiotic ribosomes or disturbance of permeability of a cellular membrane (two last mechanisms have smaller value). It is possible to slow down or overcome development of stability of mycobacteria to streptomycin at its combined use with other tuberku-lostatika (PASK, Ftivazidum, etc.). Reasonablly also its alternation with other antitubercular antibiotics — florimitsiny (see), Kanamycinum (see). Sinergidna concerning the majority of strains of enterococci is the combination of streptomycin with penicillin.
Broad use of streptomycin, including in a combination with penicillin, led to considerable distribution of microorganisms of different types, steady against its action. Depending on a source of allocation among a wedge, strains of escherichias 50 — 75% of streptomitsinoustoychivy cultures are found; among stafilokokk — 55 — 80%, microbes of group of a kleb-siyell — an enterobakter — 60 — 85%, pseudo-monads — 75 — 95%, protiums — 60 — 80%, streptococci, including fecal — 80 — 100%.
Owing to frequent allocation of steady gram-positive and gram-negative bacteria streptomycin at the infections caused by these activators is practically not applied, it was replaced with other antibiotics of a broad spectrum of activity.
Suppression of synthesis of protein is the cornerstone of the mechanism of antibacterial effect of streptomycin; it contacts 30S-subunit of ribosomes of a microbic cell, preventing interaction of RNA with ribosomes. Distortion of reading of a genetic code at a stage of broadcasting is followed by inclusion in synthesizable stranger polypeptide for the codons of amino acid which are available in a matrix.
The drugs C. are administered parenterally. Apply only a calcium chloride complex of streptomycin to introduction to the spinal channel. Due to the bad absorbability from went. - kish. a path streptomycin is appointed inside only at intestinal infections.
At intramuscular introduction streptomycin is quickly soaked up; the peak of concentration in blood is noted usually in 1 — 2 hour after an injection of drug. At administration of streptomycin concentration of an antibiotic in blood serum increases in usual doses in proportion to increase in a dose. At parenteral administration streptomycin is found in peritoneal and pleural liquids, a vitreous, bile, urine; in usual conditions practically does not get through a blood-brain barrier. Concentration of an antibiotic in cerebrospinal liquid at parenteral administration makes no more than 2 — 3% of the maintenance of an antibiotic in blood serum; at meningitis streptomycin gets into the spinal canal in large numbers (10 — 20% of content in blood), concentration of an antibiotic is in certain dependence on extent of inflammatory process in a meninx. In large numbers streptomycin is found in a pleural cavity, especially at acute inflammatory processes (to 50% of content in blood). At chronic suppurative processes (an empyema of a pleura) of a condition of diffusion are at a loss and the therapeutic effect is reached only at intrapleural introduction of an antibiotic after preliminary suction of contents of a pleural cavity. In a cavity of a pericardium and in synovial fluid concentration it usually makes 20 — 30% of content in blood. In peritoneal liquid at peritonitis streptomycin is found in especially high concentration (50 — 100% of content in blood). Streptomycin easily passes through a placenta, concentration of an antibiotic in blood of an umbilical vein and in an amniotic fluid reaches nearly 50% of its content in blood of mother; breast milk can contain about 100% of the maintenance of an antibiotic in blood. Concentration of streptomycin in most bodies and fabrics exceeds its content in blood. In the greatest number it contains in kidneys, in a little smaller — in lungs, a cardiac muscle, it is practically not found in a brain, a spleen, limf, nodes, a bone tissue. At normal function of a liver in high concentration (almost twice exceeding the content in blood) streptomycin is found in bile of the hepatic courses. At cholecystitis contents it in a gall bladder makes 70 — 80% of content in blood.
Streptomycin is quickly removed from an organism, without collecting, at normal function of kidneys, even after repeated introduction in high doses. The main quantity of the antibiotic (50 — 60%) entered intramusculary is removed with urine during 12 — 24 hours by glomerular filtering, about a half of the streptomycin emitted with urine — within the first 2 — 3 hour. At the same time concentration of an antibiotic in urine depending on the entered dose fluctuates within 200 — 1000 mkg/ml. At disturbance of secretory function of kidneys release of streptomycin is slowed down. At patients with an anury time of decrease in concentration of an antibiotic in in blood for 50% is extended to the 110th hour. In these conditions in connection with accumulation of an antibiotic in an organism even small doses of drug can cause heavy neurotoxic and nephrotoxic reactions. Pharmacokinetics of dihydrostreptomycin same, as at streptomycin.
Use of streptomycin in clinic
is Most often applied streptomycin sulfate. It is the main antitubercular drug and is used at all forms of a pulmonary tuberculosis (infiltrative and destructive, hematogenous disseminated, tubercular pneumonia, etc.), tuberculosis limf, nodes, a throat, a trachea, bronchial tubes, intestines, urinogenital bodies, serous covers, bones, joints, eyes, skin. Streptomycin sulfate is applied also at treatment of a tularemia, plague, brucellosis, bacterial endocarditis, peritonitis, infection of the uric ways, intestinal infections and other diseases caused by activators, sensitive to it. Due to the bystry emergence of stability it is recommended to define repeatedly in the course of treatment sensitivity of activators to an antibiotic. At earlier treated patients with streptomycin it is necessary to appoint it only after laboratory confirmation of sensitivity of the allocated microorganisms.
At the combined use of streptomycin with other antibiotics medicinal stability develops much more slowly (see Jiekarstvennaya stability of microorganisms). Due to the wide spread occurance of streptomitsinoustoychivy strains of gram-positive and gram-negative microorganisms — activators of pyoinflammatory processes, indications to its appointment at treatment of infections of not tubercular etiology are sharply limited.
At tuberculosis of streptomycin sulfate is applied in a complex with PASK, Ftivazidum and other tuberculostatic drugs of the first or second row. Unacceptably combined use of drug with Kanamycinum (see) or florimitsiny (see) owing to possible summation of neurotoxic effect. Streptomycin sulfate is appointed intramusculary, locally, in the form of aerosols, vnutritrakhealno, vnutrikostno, in a cavity, inside. Intramusculary the adult an antibiotic enter in a dose 0,5 — 1 g the Highest single dose of 1 g, the highest daily 2 g. For patients with body weight less than 50 kg and persons are more senior than 60 years the daily dose usually shall not exceed 0,75 g. To children drug is appointed depending on age: up to 3 months of 0,01 g/kg; from 3 to 6 months of 0,015 g/kg; from 6 months to 2 years of 0,02 g/kg; up to 4 years the highest single dose of 0,15 g, the highest daily dose of 0,3 g; 5 — 6 years the highest daily dose of 0,3 g, 7 — 9 years the highest daily dose of 0,4 g, 10 — 14 years the highest daily dose of 0,5 g.
At treatment of the infections caused by gram-negative and gram-positive microorganisms, the daily dose is entered fractionally, into 3 — 4 receptions, with an interval of 6 — 8 hour. At tuberculosis introduction of all daily dose is admissible once a day. However in the first 2 — 3 days of treatment the antibiotic is entered on 0,5 g by 2 times a day. To children at tuberculosis drug is appointed at the rate of 10 — 20 mg/kg, but by no more than 1 g a day. The course dose of drug is established individually / for each patient depending on character and a form of a disease, efficiency of treatment and portability of drug.
Use of streptomycin of sulfate is limited at the phenomena of hypersensitivity of patients to drug, functional frustration of acoustical and vestibular devices. It is applied with care at disturbance of secretory function of kidneys, at severe forms of an idiopathic hypertensia, after the postponed myocardial infarction. Treatment of streptomycin sulfate should be carried out under careful medical observation, systematically investigating in the course of treatment function VIII of couple of cranial nerves, a condition of secretory function of kidneys, gematol. indicators. At patients with the broken secretory function of kidneys the daily dose shall not exceed 0,5 g at clearance of endogenous creatinine of 50 — 60 ml/min. and 0,4 g at decrease in glomerular filtering to 40 ml/min. Streptomycin sulfate is produced in bottles on 250, 500. mg and 1 Mr.
Streptosulmitsin sulfate on antibacterial activity and chemotherapeutic action does not differ from streptomycin of sulfate, its advantage is smaller general toxicity. Indications to use of a streptosulmitsin of sulfate the same, as for streptomycin of sulfate. Streptosulmitsin sulfate is applied intramusculary in a single dose of 0,5 — 1 g the Highest single dose of 1 g, the highest daily 2 g. To children up to 3 months drug appoint in a daily dose 10 mg/kg, from 3 to 6 months of 15 mg/kg, from 6 months to 14 years of 20 mg/kg (no more than 1 g a day). The daily dose of drug at treatment of tuberculosis is entered 1 time a day or distributed on two receptions. Streptosulmitsin sulfate is let out in bottles on 0,25; 0,5 and 1 g
the Hlorkaltsmevy complex of streptomycin on an action spectrum, pharmakol. to properties, features of pharmacokinetics does not differ from streptomycin of sulfate. It is applied at treatment of meningitis of a tubercular etiology in cases of its late diagnosis and a heavy current, and also at intolerance of drugs of hydrazide isonicotinic to - you are (GINK). The calcium chloride complex of streptomycin is entered intramusculary and endo-lyumbalno. To children at meningitis it is entered into the spinal canal in the following doses: up to 3 years 0,01 — 0,015 g; from 3 to 7 years 0,015 — 0,025 g; from 7 to 14 years 0,03 — 0,05 g. For adults the daily dose of a calcium chloride complex of streptomycin makes 0,075 — 0,15 g. Total number of endolumbar administrations of drug shall not exceed 10. For introduction to the spinal channel use only freshly cooked sterile isotonic solution of sodium chloride or sterile distilled water (2 — 3 ml). At intramuscular introduction the single dose of adults makes 0,5 — 1 g, daily 1 g, the highest daily dose of 2 g. Drug is produced in bottles on 0,1, 0,2 and 0,5 g
Krom of two main dosage forms on the basis of streptomycin (streptomycin of sulfate, a calcium chloride complex of streptomycin), produce also combined salts on its basis: strepto-Saluzidum (monosulphate of streptomi-tsinovy salt of 2-carboxy-3,4-di-metoksibenzal-i of a zonikotinoa of l - hydrazone) and streptogink-paskat (a pas-raaminosalitsnlovaya стрептоми-циллиден-изоникотиноилгидразона salt). Indications to purpose of these drugs the same, as at use of other dosage forms of streptomycin.
Streptosalyuzid it is the most reasonable to appoint when use of other antitubercular drugs is impossible or is followed by side reactions. Streptosalyuzid apply intramusculary it is, intra-trakhealno, inhalation. The adult the drug is administered intramusculary by 0,5 — 2 g a day at one time. Daily doses for children from 3 to 5 years 0,25 — 0,3 g; from 6 to 9 years 0, 4 — 0,5 g; from 10 to 12 years 0,6 — 0,7 g; from 13 to 15 years 0,08 — 0,09 g. Drug is produced in bottles on 0,5 and 1 g
of Streptogink-paskat use at treatment of the forms of tuberculosis caused by the mycobacteria sensitive to streptomycin and drugs of the GINK group. Enter intramusculary, a daily dose for adult 2 g. Drug is produced in bottles on 0,5 and 1 Mr.
Digidrostreptomitsin release in the form of his p-aminosalicylic salt Pasomycinum (see). It is the most reasonable to apply Pasomycinum at the tuberculosis which is combined with diseases went. - kish. a path when reception of PASK inside is followed by side reactions. Resistance of mycobacteria to Pasomycinum develops more slowly, and degree is lower than it, than streptomycin resistance and PASK. Drug is appointed the adult intramusculary, in a cavity, locally in a daily dose of 1 g, to children — depending on age. Produce in bottles 0,5 and 1 g
the Table. ANTIMICROBIC RANGE of STREPTOMYCIN
Bibliography: Navashin S. M. of ifomi-N and I. P. Rational antibioticotherapia, page 216, M., 1982.
S. M. Navashin, I. P. Fomina.