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Erythromycin was discovered in 1952 by McGuire and his collaborators in the metabolic products of Streptomyces erythreus. This microorganism was isolated from a soil sample taken in the Philippines. Clarithromycin and azithromycin are semisynthetic derivatives of erythromycin.
Macrolides (erythromycin, clarithromycin and azithromycin) derive their name from the macrocyclic lactone ring with which at least one deoxysaccharide is bound. Clarithromycin differs from erythromycin by a methyl group substituting hydrogen for the hydroxyl group at position 6, and in azithromycin, the lactone ring contains an additional nitrogen atom with a methyl group attached to it. Due to these structural differences, azithromycin and clarithromycin are more stable in an acidic environment, better penetrate into tissues and have a broader spectrum of action
Mechanism of action
Macrolides are bacteriostatic antibiotics that suppress protein synthesis by reversible binding to the 505 subunit of ribosomes. Macrolides act on the same target as chloramphenicol, competitively inhibiting its binding to ribosomes. The change in the 50S subunit of the ribosomes due to a mutation, which disrupts the binding of macrolides to the target, leads to the development of drug resistance. In contrast to chloramphenicol, which prevents the formation of a peptide bond, macrolides act at the stage of translocation – the transfer of the newly synthesized peptidyl-tRNA molecule and the aminoacyl segment of the ribosome to the peptidyl region.
Gram-positive bacteria accumulate almost 100 times more erythromycin than gram-negative bacteria.
In the alkaline medium, the antimicrobial activity of the preparation is much higher, probably because in a non-ionized form that predominates at high pH, it penetrates to bacterial cells much better.
Acquired resistance to macrolides is due to three main mechanisms:
- active excretion of the drug from the cell (in staphylococci the carrier is encoded by the gene mrsA, in the Streptococcus pyogenes gene mefA, in Streptococcus pneumoniae – the mefE gene)
- a decrease in the affinity of the ribosomes to the drug due to their methylation under the action of an induced or constitutive methyltransferase enzyme (this enzyme is encoded by the genes ermin, erbB and ermin)
- hydrolysis of macrolides by esterases of enterobacteria (Barth61dmy et al., 1984).
The second mechanism, mediated by the genes ermin, causes stability not only to macrolides, but also to lincosamides and streptogramins (phenotype MLSB). All these drugs act on the same target, the methylation of which leads to the formation of resistance. There is another mechanism of resistance to macrolides, found in Bacillussubtilis, Campylobacter spp. and Gram-positive cocci. It is caused by chromosomal mutations that alter the structure of the protein of the 508 subunit of the ribosomes.
Application of azithromycin
Depending on the pathogen and the severity of the infection, the dose of erythromycin for oral administration in adults is usually 1-2 g / day in several doses (usually the drug is taken every 6 h). Even at a dose of 8 g / day inside for 3 months, erythromycin is well tolerated. If possible, erythromycin and erythromycin stearate should not be taken immediately before meals and immediately after it (this does not apply to erythromycin estolate and erythromycin ethyl succinate). In children, the daily intake for oral administration is 30-50 mg / kg in 4 divided doses; with severe infections it can be doubled. Intramuscular injection is not recommended, since injections are painful. Preparations for intravenous administration (erythromycin glucoheptonate or erythromycin lactobionate) are used in severe infections, such as Legionnaires’ disease. The usual dose is 0.5-1 g IV every 6 hours. In the treatment of erythromycin with glucoheptonate at a dose of 1 g IV every 6 hours for 4 weeks, no significant side effects were observed, with the exception of thrombophlebitis at the venipuncture site.
Clarithromycin is released in the form of tablets, powder for the preparation of a suspension for ingestion and powder for the preparation of an injection solution. The drug is usually prescribed 2 times a day. For mild and moderate infections in children older than 12 years and adults, a single dose is 250 mg. If the infection is severe (for example, pneumonia) or caused by a microorganism for which clarithromycin is not very active, a single dose is increased to 500 mg. In clinical trials, children less than 12 years of age were prescribed 7.5 mg / kg 2 times a day. Tablets long-acting, containing 500 mg of clarithromycin, take 2 pieces 1 time per day.
Azithromycin is released in the form of tablets, suspension for ingestion and powder for the preparation of an injection solution. Inside the drug given for 1 hour before meals or 2 hours after eating. In the treatment of community-acquired pneumonia, pharyngitis, skin and subcutaneous tissue infections on an outpatient basis, a saturating dose of 500 mg is given on the first day, and a maintenance dose of 250 mg / day from day 2 to day 5. For treatment and prevention of infection, patients with AIDS use higher doses. At the same time for therapeutic purposes, azithromycin is prescribed at a dose of 500 mg / day in combination with one or more other drugs. For primary prevention of this infection, azithromycin is taken at a dose of 1200 mg I once a week. In uncomplicated non-gonococcal urethritis, 1 g of azithromycin is administered once. In a dose of 2 g once the drug is effective in gonorrhea, this nose is not widely used for this purpose.
Children azithromycin is prescribed as a suspension for oral administration. With acute otitis media and pneumonia, 10 mg / kg (not more than 500 mg) are given on the first day, and 5 mg / kg / day (no more than 250 mg / day) for the next 4 days. With angina and pharyngitis, azithromycin is taken at a dose of 12 mg / kg / day (not more than 500 mg / day) for 5 days.
Mycoplasma infections. Erythromycin (500 mg orally 4 times a day) reduces the duration of fever, and with myco-plasma pneumonia, promotes faster normalization of the radiographic pattern (Rasch and Mogabgab, 1965). In case of intolerance of oral administration, erythromycin is given IV. With mycoplasmal infections, other macrolides and tetracyclines are also effective.
Legionnaires’ disease. Erythromycin, which was previously the drug of choice for pneumonia caused by Legionella pneumophila Legionella micdadei and other representatives of Legionella spp, is now replaced by azithromycin and fluoroquinolones. Azithromycin is highly active against legionella in vitro, accumulates in tissues at higher concentrations than erythromycin is convenient in use (it is prescribed once a day) and is better tolerated. The dose is 500 mg orally or IV for 10-14 days.
Side effects of Azithromycin
Erythromycin rarely causes severe side effects. Allergic reactions include fever, eosinophilia and rash, which can be observed individually or in combination with each other. After the drug is discontinued, the symptoms quickly disappear. The most serious side effect is cholestatic hepatitis. It is caused mainly by erythromycin estolate, very rarely – erythromycin ethyl succinate or erythromycin stearate. The disease begins approximately 10-20 days after the beginning of treatment with nausea, vomiting and cramping pain in the abdomen. The pain is often the same as when | acute cholecystitis, which may serve as an excuse for unnecessary surgical intervention. Soon there is jaundice, sometimes accompanied by fever, leukocytosis, eosinophilia and increased activity of aminotransferases. When liver biopsies are detected, cholestasis, periportal infiltration by neutrophils, lymphocytes and eosinophils, and sometimes necrosis of hepatocytes. Manifestations of hepatitis rarely persist longer than several days after drug withdrawal. Perhaps, cholestatic hepatitis occurs as a result of an allergic reaction to erythromycin estolate. Perhaps a slight increase in the activity of hepatic enzymes in the serum.
When ingestion, especially in large doses, erythromycin often causes epigastric pain, sometimes quite severe. With iv introduction, gastrointestinal disturbances are also possible – cramping pain in the abdomen, nausea, vomiting, diarrhea. It is shown that erythromycin enhances motility of the gastrointestinal tract, binding to the receptors of motilin. Gastrointestinal disorders are dose-dependent and are more common in children and young people. Longer infusion (within 1 h) and the prescription of glycopyrrogenation of bromide soften these symptoms. IV injection of the drug at a dose of 1 g, even when diluted in a large volume of fluid, is often accompanied by thrombophlebitis. With a slow introduction, the risk of this complication is reduced.
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