ACTUAL INFORMATION It was 1980 that Dr. Slobodan Rokic and his research team from Pliva (a pharmaceutical company in Croatia) discovered Azithromycin. A patent for it was received in a year. And then, using the Pliva license, Pfizer launches the drug on the pharmaceutical markets and already under a completely different brand name. And this happens after 10 years. A few more years passed. And they approved a new azithromycin lectform for the treatment of eye infections. Azithromycin is practically insoluble in water and freely soluble in anhydrous ethanol and methylene chloride. Azithromycin is a macrolide antibiotic. This is a semi-synthetic derivative of erythromycin. Azithromycin differs from erythromycin by the addition of a methyl-substituted nitrogen atom in the lactone ring. This structural modification increased the acid resistance of the compound and improved the penetration of the drug molecule into the tissue, expanding its spectrum of action. Macrolides are usually distinguished by their active action, cover a wide range of gram-positive and gram-negative bacteria, including intracellular pathogens, such as Chlamydia and Legionella. They exhibit their antibiotic activity by binding to the 50S ribosome (its subunit) and inhibiting protein synthesis. Pharmacology and azithromycin therapy Azithromycin has been found to be less active against erythromycin against gram-positive bacteria, but its effect is more significant against some gram-negative organisms, such as Haemophilus influenzae, Moraxella catarrhalis, and also has activity against some enterobacteria, such as Escherichia coli and Salmonella and Shigella species, and also against Legionella pneumophila, B. burgdorferi, Mycoplasma pneumoniae. It (azithromycin) has increased activity against Mycobacterium avium-intracellulare, as well as some protozoa (for example, the species Cryptosporidium and Plasmodium), an excellent action against Toxoplasma gondii, kills cysts. It is more active than erythromycin against Chlamydia trachomatis and Ureaplasma urealyticum. Mechanism of action. It is a bacteriostatic agent that inhibits protein synthesis by reversibly binding to the 50S ribosomal subunits of sensitive microorganisms. The cells of the body are significantly more permeable to the dosage form of the drug, which is likely to exhibit increased antimicrobial activity at alkaline pH. Macrolide resistance. As a rule, resistance to macrolides is due to the following mechanisms: ribosomal protection by inducible or constitutive production of methylase enzymes, mediated by expression (ermA), (ermB) and (ermC), which modify the ribosomal target and reduce drug binding; hydrolysis of esterases produced by Enterobacteriaceae; chromosomal mutations that alter the protein of the 50S ribosome subunit (observed in B. subtilis, Campylobacter species, mycobacteria, and gram-positive cocci). Action other than antimicrobial effects. In studies, the activity of Azithromycin as a promising drug for the treatment of gastroparesis and gastrointestinal motility disorders was indicated. One study showed that azithromycin may be effective against bronchial asthma (late onset). Information was obtained on the effectiveness of azithromycin against malaria, provided that it was combined with artemisinin or quinine sulfate. Azithromycin-artemisinin, even if taken only 1 time per day (3 days), and azithromycin-quinine sulfate - 3 times a day. These drug combinations were relatively safe and effective for uncomplicated malaria, and they deserve further study in specific patient groups. Coronary heart disease: macrolide antibacterial agents, including azithromycin. Clarithromycin, roxithromycin, azithromycin have been investigated for the prevention of coronary heart disease, based on the alleged association between atherosclerosis and Chlamydophila pneumoniae (Chlamydia) infection. Although the preliminary results of some experimental studies were promising, long-term studies on a large number of patients were disappointing, and none of the three macrolides reduced ischemic effects or provided a clinical effect. In one study, an unexpected increase in mortality from cardiovascular disease was observed with clarithromycin. Gingival hyperplasia: azithromycin has a positive effect on the treatment of gingival hyperplasia, which was caused by the intake of cyclosporine, especially with its early introduction (azithromycin) into the inflammation process. Cystic fibrosis: azithromycin is widely used for cystic fibrosis, with evidence showing a decrease in lung function and exacerbations. This immunomodulatory therapy is likely to interfere with the growth of Pseudomonas aeruginosa biofilm. Clinical use and dosage. Clinically, azithromycin is used as follows: 1. respiratory tract infections; 2. infections of the skin and soft tissues; 3. chlamydial infections; 4. mild or moderate non-gonococcal urethritis; 5. otitis media; 6. typhoid fever due to multiple antibacterial-resistant organisms; 7. prevention of group A streptococcal infection; 8. as a preventive treatment of bacterial endocarditis in patients undergoing dental procedures with a high risk of developing endocarditis; 9. whooping cough; 10. mycobacterial infections. Treatment or prevention of mycobacterium avium-intracellular infection in AIDS patients, which requires higher doses: 600 mg per day in combination with one or more other drugs for treatment or 1200 mg 1 time per week for primary prevention. Azithromycin is prescribed in the treatment of sexually transmitted diseases, especially during pregnancy, when tetracyclines are contraindicated. The treatment for uncomplicated non-gonococcal urethritis, presumably caused by C. trachomatis, is to take a single dose (1 g) of azithromycin. This dose is also effective for chancroid. Azithromycin (1 g / week for 3 weeks) is an alternative regimen for the treatment of inguinal or venous lymphogranulomas. Uncomplicated genital chlamydial infections and non-gonococcal urethritis, 1 g in a single dose. Typhoid fever, 500 mg 1 time per day (total number of days of taking the drug - 7). ADME profile (absorption, distribution, metabolism, and excretion - absorption, distribution, metabolism and excretion). Azithromycin, administered orally, is rapidly absorbed and distributed widely throughout the body except the brain and cerebrospinal fluid. The peak concentration in plasma is reached after 2-3 hours after oral administration. A loading dose of 500 mg will give a peak plasma concentration of the drug of 0.4 g / ml. When the loading dose is 250 mg once a day for 4 days, then in a stationary state the peak concentration of the drug is 0.24 g / ml. Azithromycin can also be administered intravenously, creating plasma concentrations of 3-4 g / ml after a 1-hour infusion of 500 mg. Absorption from capsules decreases with food. The unique pharmacokinetic properties of the drug lie in the extensive redistribution in tissues and high concentrations of the drug in the cells (including phagocytes). This leads to an increase in the concentration of the drug in the tissues, when compared with simultaneous concentrations in the blood serum. Tissue fibroblasts act as a natural reservoir for in vivo drugs. Animal studies show that azithromycin crosses the placenta. At very low plasma concentrations, this makes up 50% of the amount of protein. Azithromycin undergoes demethylation in the liver to an inactive metabolite, but excretion is carried out by the biliary tract - the main way. Only 12% of the drug is excreted unchanged in the urine. Half-life (T½) - 40–68 hours Adverse Reactions Anorexia, dyspepsia, flatulence, dizziness, headache, drowsiness, cramps, arthralgia and impaired taste and smell; rarely - constipation, hepatitis, liver failure, fainting, insomnia, agitation, anxiety, asthenia, paresthesia, hyperactivity, thrombocytopenia, hemolytic anemia, interstitial nephritis, acute renal failure, photosensitivity, bleaching of the lips and tongue. Drug interaction. It is not recommended to use Azithromycin in combination with antacids containing aluminum or magnesium. Salts may decrease the rate, but not the extent of its absorption; Azithromycin should be prescribed at least 1 hour before or 2 hours after antacid. Serum azithromycin concentrations increase markedly when it is given with nelfinavir. Azithromycin in capsules should not be administered with food, because this leads to a decrease in the availability of the drug itself. Azithromycin may enhance the anticoagulant effect of coumarins. Azithromycin may increase the concentration of theophylline in blood plasma (Bakheit A.H., 2014). Systematic reviews contain a wealth of information about the use and safety of azithromycin in various therapeutic areas. We provide information on several studies that, in our opinion, may be of interest. Long-term azithromycin therapy has been shown to reduce exacerbations of chronic obstructive pulmonary disease (COPD) and is prescribed in accordance with the latest recommendations for patients with COPD who are at risk of recurrent exacerbation. However, concerns about adverse effects limit its widespread distribution. Doctors deciding whether long-term azithromycin therapy should be used should evaluate the individual risk of cardiovascular complications in each patient and the individual and population effects of macrolide resistance compared to the expected benefits. This review will summarize the efficacy and safety of chronic azithromycin for the prevention of exacerbations of COPD (Taylor S.P., 2015). The FDA has updated the labeling of azithromycin packaging to include the risk of prolonged repolarization of the heart and lengthening of the Q – T interval, which increases the likelihood of cardiac dysarrhythmias, especially in the elderly. The update was initiated by a study that revealed an increased risk of death in patients taking azithromycin compared with patients taking amoxicillin. However, the cardiovascular results of other studies of azithromycin were inconsistent, so more research is needed. At the same time, specialists should recognize that azithromycin plays a role in the treatment of bacterial infections, and should prescribe an antibiotic if necessary (Sutton S.S., 2017). Azithromycin is widely used as a first-line drug for the treatment of children with mycoplasma pneumonia, although in the pediatric ward, children often experience vomiting as a result of oral administration. It is believed that drugs that are administered rectally enter the circulatory system without first passing through the liver. Therefore, 5 healthy volunteers were included in the study. All participants gave written informed consent to participate in the study. Randomly prescribed either oral administration of a tablet of Azithromycin 500 mg, or rectal administration of a suppository of the same drug 125; 250 or 500 mg. Blood samples for serum preparation were taken before and after 1; 2; 3; 4; 6; 12 and 24 hours after the first rectal dose. Serum azithromycin concentrations were determined by high performance liquid chromatography (HPLC) with electrochemical detection. Thus, the bioavailability of the suppository during rectal administration was 20.3% compared with oral administration. It is assumed that the surface area where the active substance is absorbed also affects the absorption during rectal administration. Although further research is needed to improve the absorption of the substance in the rectum and ensure the safety of children, suppositories with azithromycin may already be an effective tool in cases where oral administration is not allowed (Maeda M. et al., 2016).

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