Modern macrolides in the treatment of community-acquired pneumonia

Antibiotics of the macrolide group are extremely often prescribed in therapeutic practice. This is quite justified - in the modern world, with such a variety of antibacterial drugs, preference should be given to those that have a minimum of side effects undesirable for the patient, and macrolide antibiotics are usually well tolerated by patients.

In order to improve the safety profile, antibiotics of the macrolide group with an additional prebiotic component were developed - Ecoantibiotics. These drugs have an additional beneficial effect on the state of the intestinal microflora, thereby improving the tolerability of antibacterial therapy. The group of macrolides includes ecoantibiotics Ecomed (azithromycin) and Ecositrin (clarithromycin).

Antibiotics from the macrolide group

Macrolides are drugs, antibiotics, the chemical composition of which is complex: to be more precise, these are solid substances similar in their properties to lactones; their structure contains a macrocyclic lactone ring

Depending on the number of carbon atoms in the ring, macrolides are divided into 14-membered ones, which include erythromycin, roxithromine and clarithromycin; 15-membered - azithromycin and 16-membered - midecamycin, spiramycin, josamycin.

The main purpose of macrolides is activity against intracellular pathogens, such as chlamydia, mycoplasma, legionella and campylobacter; macrolides also show activity against gram-positive cocci (streptococci and staphylococci).

Spectrum of activity of macrolide antibiotics

Macrolides are broad-spectrum antibiotics. They show high activity against gram-positive cocci (S.pyogenes, S.pneumoniae, S.aureus), only MRSA is not included in this group. Also, macrolide antibiotics are used to eradicate the pathogens of whooping cough and diphtheria, Legionella, Moraxella, Campylobacter and Listeria. Macrolides are often indispensable for diseases caused by spirochetes, ureaplasmas, chlamydia and mycoplasmas. The use of macrolides is also effective for anaerobic infections (except for cases of infection with B.fragilis).

It is important to note that azithromycin (belonging to semi-synthetic drugs) has a stronger effect on Pseudomonas aeruginosa than others in the group of macrolides. In turn, clarithromycin is superior to other drugs in its effect on Helicobacter pylori and atypical mycobacteria.

Some macrolide antibiotics (azithromycin, spiramycin and roxithromycin) are active against protozoa such as Toxoplasma gondii and Cryptosporidium spp..

It is important to remember that a number of microorganisms are not sensitive to macrolide antibiotics. These include bacteria of the Enterobacteriaceae, Pseudomonas and Acinetobacter families.

Pharmacokinetics of macrolides

Macrolides, after oral administration, behave differently: it all depends on the type of drug and the presence of food at the time of taking the antibiotic, which can reduce the bioavailability of, for example, erythromycin, and to a lesser extent affect the absorption of antibiotics such as azithromycin and roxithromycin. At the same time, among macrolides there are antibiotics whose pharmacokinetics are not related to food intake - clarithromycin, spiramycin and josamycin.

Plasma protein binding among macrolides also varies. The highest concentrations of the antibiotic in the blood serum are observed after taking roxithromycin, since more than 90% of the drug is bound to blood proteins. For spiramycin this figure is minimal - 20%.

The distribution of macrolide antibiotics in the body occurs by creating high concentrations in the tissues of the body. These drugs are able to accumulate at the site of inflammation and quickly suppress the infection. In this case, the most active macrolides should be considered azithromycin and clarithromycin, which are capable of suppressing inflammation in the early stages, even long-term, since they create high tissue concentrations of the active substance. At the same time, it should be noted that drugs from the macrolide group have a positive effect on inflammatory factors, ensuring their direct anti-inflammatory effect of these antibiotics.

An important advantage of macrolide antibiotics is their ability to penetrate the cell wall, which ensures their activity against intracellular pathogens, which is especially important in the treatment of infections caused by atypical pathogens and STDs.

The process of macrolide metabolism occurs, in turn, mainly through the liver with the participation of cytochrome P-450. Metabolites are excreted mostly through bile; 5 to 10 percent is excreted through the kidneys; T1/2 varies for different molecules and ranges from 1 hour for medicamicin to 55 hours for azithromycin. In liver cirrhosis, the half-life of drugs such as erythromycin and josamycin can significantly increase; the prescription of these macrolides for this pathology requires special precautions. However, renal failure has virtually no effect on the half-life of macrolide antibiotics. The only exceptions are clarithromycin and roxithromycin.

Antibiotics of the macrolide group are practically unable to overcome the blood-brain and blood-ophthalmic barriers. The hematoplacental barrier is passable for macrolides, and they are also able to penetrate into breast milk, which imposes some restrictions on their use during pregnancy and breastfeeding, despite the lack of a teratogenic effect.

V.V. Kosarev, S.A. Babanov State Educational Institution of Higher Professional Education "Samara State Medical University"

Key words: macrolides, antimicrobial activity, pharmacokinetics, indications for use, drug interactions.

Currently, there is increased interest in the use of macrolides in clinical and outpatient practice for the treatment of infections in pulmonological and otorhinolaryngological practice. Macrolides are included in domestic recommendations for the management of patients with widespread community-acquired infections, in particular sinusitis, otitis, and community-acquired pneumonia; Moreover, they are not only formally a means of empirical therapy for these diseases, but actually occupy a leading place both in the preferences of doctors and in real everyday prescriptions [1-8]. The basis of the chemical structure of macrolides is the macrocyclic lactone ring; Depending on the number of carbon atoms it contains, 14-membered (erythromycin, clarithromycin, roxithromycin), 15-membered (azithromycin) and 16-membered (spiramycin, josamycin, midecamycin) macrolides are distinguished. The spectrum of antimicrobial activity covers almost all respiratory bacterial pathogens, including atypical microorganisms that are naturally resistant to β-lactam antibiotics. All macrolides are characterized by a predominantly bacteriostatic effect, activity against gram-positive cocci (streptococci, staphylococci) and intracellular pathogens (mycoplasma, chlamydia, legionella), high concentrations in tissues (5-10-100 times higher than plasma concentrations), low toxicity, absence of cross-allergy with β-lactams. Macrolides in subinhibitory concentrations can reduce the production of alginate (it ensures the adhesion of bacteria on biological surfaces) and the mobility of P. aeruginosa and Proteus mirabilis, thereby reducing the degree of colonization and biofilm formation. Macrolides belong to “tissue” antibiotics and accumulate most intensively in the tonsils, lymph nodes, middle ear, paranasal sinuses, lungs, bronchial secretions, pleural fluid, and pelvic organs. Macrolide group drugs penetrate granulocytes, monocytes, alveolar macrophages, fibroblasts and are delivered by them to the site of infection, where they create concentrations many times higher than the minimum inhibitory concentrations for sensitive microorganisms. Modern macrolides, unlike other antimicrobial drugs, have anti-inflammatory, immunomodulatory and mucoregulatory properties. They have a beneficial effect on phagocytosis, chemotaxis, killing and apoptosis of neutrophils, and inhibit the oxidative “burst” - the formation of highly active oxidizing compounds, primarily NO, that can damage their own tissues. Interacting with polymorphonuclear neutrophils, lymphocytes, eosinophils, monocytes, macrolides suppress the synthesis and secretion of pro-inflammatory cytokines - interleukins (IL) - IL-1, IL-6, IL-8, tumor necrosis factor α and enhance the secretion of anti-inflammatory cytokines - IL- 2, IL-4, IL-10. They reduce the viscosity and elasticity of bronchial and nasal secretions and are able to reduce sputum production in patients with excessive sputum secretion. Azithromycin has the highest degree of penetration into polymorphonuclear neutrophils and lingers in them much longer compared to clarithromycin and erythromycin, which greatly increases the ability for phagocytosis and anti-infective protection. Azithromycin causes degranulation of neutrophils and stimulates the oxidative burst (oxygen consumption necessary for the functions of macrophages). Evidence of neutrophil degranulation is an increase in the level of lysosomal enzymes in the blood plasma and a decrease in macrophages after taking the first dose of azithromycin. Erythromycin, the first natural macrolide, is still widely used; it acts on remolytic streptococci of group A, pneumococci (except penicillin-resistant), staphylococci (including PRSA), intracellular microorganisms (chlamydia, mycoplasma, legionella, campylobacter), pathogens of whooping cough, diphtheria. Inactive against Haemophilus influenzae. When taken orally, the drug is partially inactivated in the acidic environment of the stomach, so bioavailability can vary from 30 to 60% and is significantly reduced in the presence of food. It penetrates poorly through the BBB, is metabolized in the liver, and is excreted primarily through the gastrointestinal tract. The half-life is from 1.5 to 2.5 hours. It is used for streptococcal infections in patients with allergies to penicillins (tonsillopharyngitis, scarlet fever, prevention of rheumatic fever). Erythromycin can be used for campylobacteriosis, for routine “sterilization” of the intestine before surgery (in combination with neomycin or kanamycin), community-acquired pneumonia, diphtheria, whooping cough, periodontitis, skin and soft tissue infections, chlamydial infection, mycoplasma infection, legionellosis. Erythromycin is used orally - 0.25-0.5 g every 6 hours 1 hour before meals; for streptococcal tonsillopharyngitis - 0.25 g every 8-12 hours for 10 days; for the prevention of rheumatic fever - 0.25 g every 12 hours; 0.5-1.0 g intravenously every 6 hours. The antimicrobial activity of oleandomycin is less than that of erythromycin, and it is also less well tolerated by patients, so the drug is prescribed very rarely. Unlike erythromycin, azithromycin is active against H. influenzae (including β-lactamases producing). Azithromycin is active against aerobic gram-positive bacteria: Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus spp. groups C, F and G, Streptococcus viridans, Staphylococcus aureus; aerobic gram-negative bacteria: Haemophilus influenzae, Moraxella catarrhalis, Bordetella pertussis, Bordetella parapertussis, Legionella pneumophila, Haemophilus ducrei, Helicobacter pylori, Campylobacter jejuni, Neisseria gonorrhoeae and Gardnerella vaginalis; anaerobic bacteria: Bacteroides bivius, Clostridium perfringens, Peptostreptococcus spp. The drug is active against intracellular microorganisms: Chlamydia trachomatis, Mycoplasma pneumoniae, Ureaplasma urealyticum, Borrelia burgdorferi, as well as against Treponema pallidum. Azithromycin is superior to other macrolides in activity against H. influenzae and M. catarrhalis. Macrolides do not act on oxacillin-resistant staphylococci and enterococci, gram-negative bacteria of the Enterobacteriaceae family, P. aeruginosa, Acinetobacter spp. and other non-fermenting bacteria. After oral administration of azithromycin at a dose of 500 mg, the maximum concentration (Cmax) in the blood plasma is reached after 2.5-2.96 hours and is 0.4 mg/l. The main sites for creating high and stable concentrations of azithromycin are lung tissue, bronchial secretions, sinuses, tonsils, middle ear, prostate, kidneys and urine. When taking the same dose, the concentration of azithromycin in the bronchial mucosa is 200 times higher than the serum concentration in bronchoalveolar secretions. Thus, azithromycin compares favorably with other macrolides in creating high concentrations in the foci of infections - 30-50, and according to some data 100 times, more than in serum. In patients with renal and hepatic insufficiency and in the elderly, the pharmacokinetics do not change significantly, which makes it possible to use it without apparent concern. In its ability to penetrate histohematic barriers (except the blood-brain barrier), azithromycin is superior to beta-lactams and aminoglycosides. In vitro and in vivo models have shown that azithromycin is taken up and delivered to the site of infection by polymorphonuclear leukocytes and macrophages. The structure of the antibiotic molecule (the presence of a nitrogen atom, which is absent in 14- and 16-membered macrolides) ensures a strong connection with the acidic organelles of the cell and the longest half-life of the drug (48-60 hours depending on the dose of azithromycin), which allows it to be taken once a day . In this case, the post-antibiotic effect persists for 7-10 or more days after completion of a 3-5-day course of oral administration at a standard dose. Distribution. Azithromycin penetrates well into the respiratory tract, organs and tissues of the urogenital tract, into the prostate gland, into the skin and soft tissues. The high concentration in tissues (10-50 times higher than in blood plasma) and long T1/2 are due to the low binding of azithromycin to plasma proteins, as well as its ability to penetrate eukaryotic cells and concentrate in the low pH environment surrounding lysosomes. This, in turn, determines the large apparent Vd (31.1 l/kg) and high plasma clearance. The ability of azithromycin to accumulate predominantly in lysosomes is especially important for the elimination of intracellular pathogens. It has been proven that phagocytes deliver azithromycin to sites of infection, where it is released during the process of phagocytosis. The concentration of azithromycin in foci of infection is significantly higher than in healthy tissues (on average by 24-34%) and correlates with the degree of inflammatory edema. Indications for the use of azithromycin are infections of the upper respiratory tract with allergies to penicillins (streptococcal tonsillopharyngitis, acute sinusitis), infections of the upper respiratory tract (exacerbation of COPD, community-acquired pneumonia), orodental infections, infections of the skin and soft tissues, chlamydial infection, mycoplasma infection, prevention of atypical mycobacteriosis in AIDS, scarlet fever. For adults with infections of the upper and lower respiratory tract, azithromycin is prescribed 500 mg per day for 3 days; course dose – 1.5 g. For infections of the skin and soft tissues, 1 g is prescribed on the 1st day, then 500 mg daily from the 2nd to the 5th day; course dose - 3 g. For acute uncomplicated urethritis or cervicitis, 1 g is prescribed once. For Lyme disease (borreliosis), for the treatment of the initial stage (erythema migrans), 1 g is prescribed on the 1st day and 500 mg daily from the 2nd to Day 5 (course dose – 3 g). For diseases of the stomach and duodenum associated with Helicobacter pylori, 1 g per day is prescribed for 3 days as part of combination anti-Helicobacter pylori therapy. Adults with infections of the upper and lower respiratory tract are prescribed 500 mg/day for 3 days; course dose - 1.5 g. Roxithromycin is close to erythromycin in the spectrum of antimicrobial activity, but is characterized by stable bioavailability (50%), independent of food intake, higher concentrations in the blood and tissues, greater T1/2 (10-12 hours) , better tolerability and lower likelihood of drug interactions. It is used for streptococcal tonsillopharyngitis, acute sinusitis, exacerbation of chronic obstructive pulmonary disease, community-acquired pneumonia, orodental infections, infections of the skin and soft tissues, chlamydial and mycoplasma infections. Spiramycin is one of the first natural 16-membered macrolides. Features: active against some pneumococci and Streptococcus pyogenes, resistant to 14- and 15-membered macrolides, acts on Toxoplasma and cryptosporidium, bioavailability (30-40%) does not depend on food intake, creates higher and more stable tissue concentrations than erythromycin, T1/2 is 8-14 hours. The drug does not affect the activity of cytochrome P450 isoenzymes, and therefore does not change the metabolism of other drugs. Indications for use: infections of the upper respiratory tract with allergies to penicillins (streptococcal tonsillopharyngitis), infections of the upper respiratory tract (exacerbation of COPD, community-acquired pneumonia), orodental infections, infections of the skin and soft tissues, chlamydial infection, mycoplasma infection, toxoplasmosis, cryptosporidiosis. Midecamycin is a natural 16-membered macrolide. The spectrum of activity and other properties is similar to spiramycin (but does not affect protozoa). Indications for its use are: infections of the upper respiratory tract with allergies to penicillins (streptococcal tonsillopharyngitis), infections of the upper respiratory tract (exacerbation of COPD, community-acquired pneumonia), infections of the skin and soft tissues, urogenital infections, mycoplasma infection). Josamycin is similar in its main characteristics to other 16-membered macrolides and slightly inhibits cytochrome P450. Clinically significant interactions were recorded only when combined with carbamazepine and cyclosporine (slowing their elimination). Indications for its use are: infections of the upper respiratory tract with allergies to penicillins (streptococcal tonsillopharyngitis), infections of the upper respiratory tract, skin and soft tissues, urogenital infections. Drug interactions. 14-membered macrolides reduce the activity of the cytochrome P450 3A4 isoenzyme, and therefore slow down the hepatic metabolism of many drugs. 15- and 16-membered macrolides have little or virtually no effect on the activity of microsomal enzymes. With the simultaneous use of azithromycin and antacids (aluminum- and magnesium-containing), the absorption of azithromycin slows down. Ethanol and food slow down and reduce the absorption of azithromycin. When warfarin and azithromycin were co-administered (in usual doses), no changes in prothrombin time were detected, however, given that the interaction of macrolides and warfarin may enhance the anticoagulant effect, patients need careful monitoring of prothrombin time. The combined use of azithromycin and digoxin increases the concentration of the latter. When administered simultaneously with theophylline, carbamazepine, cyclosporine, bromocriptine, disopyramide, erythromycin increases their concentration in the blood due to inhibition of metabolism in the liver. When erythromycin is combined with lovastatin, severe myopathy and rhabdomyolysis may develop. The bioavailability of digoxin while taking erythromycin may increase due to a decrease in inactivation of digoxin by intestinal microflora. Among the undesirable reactions to erythromycin, one can highlight dyspeptic and dyspeptic symptoms (in 20-30% of patients), which are caused by stimulation of gastrointestinal motility (prokinetic, motilin-like effect), pyloric stenosis in newborns (therefore, it is preferable for them to prescribe 16-membered macrolides - spiramycin, midecamycin) . Allergic reactions when using macrolides develop very rarely. When administered intravenously, thrombophlebitis may develop (therefore, it should be administered in the highest possible dilutions and as a slow infusion). With the simultaneous use of azithromycin with ergotamine and dihydroergotamine, an increase in the toxic effect of the latter (vasospasm, dysesthesia) is observed. Co-administration of triazolam and azithromycin reduces clearance and enhances the pharmacological effect of triazolam. Azithromycin slows down the excretion and increases the concentration of plasma and the toxicity of cycloserin, indirect anticoagulants, methylprednisolone, felodipine, as well as drugs undergoing microsomal oxidation (carbamazepine, terphenin, cyclosporine, hexobarbital, aboloids of knorships, rods, valProtic acid, dysopian acidic acid, dysopian acidic acid, dysopian d, bromocriptine, phenytoin, oral hypoglycemic agents, theophylline and other xanthine derivatives) - due to the inhibition of microsomal oxidation in hepatocytes by azithromycin. Lincosamines weaken the effectiveness of azithromycin, while tetracycline and chloramphenicol enhance them. Pharmaceutically, azithromycin is incompatible with heparin.

Literature 1. Krasilnikova A.V. Comparative effectiveness of generic azithromycin for community-acquired pneumonia in adults (clinical and pharmacoeconomic aspects). Abstract of the dissertation for the academic degree. PhD degree Volgograd.2004; 24. 2. Kosarev V.V., Lotkov V.S. Babanov S.A. Clinical pharmacology. Rostov-on-Don. "Phoenix". 2008; 348. 3. Schito GC, Debbia EA, Marchese A. The evolving threat of antibiotic resistance in Europe: new data from the Alexander Project // J Antimicrob Chemother. 2000; 46: Suppl T1: 3-9. 4. Huff J., White A., Power E. et al. 10-year trends in penicillin- and erythromycin-resistant S. pneumoniae for 5 European countries and the USA. The Alexander Project. In: Abstracts from the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego, USA: American Society of Microbiology, 2002; 108. 5. Schito GC Is antimicrobial resistance also subject to globalization? // Clin Microbial Infect. 2002; 8: Suppl 3: 1-8. 6. Kozlov R.S., Krechikova O.I., Sivaya O.V. and others. Antibiotic resistance of Streptococcus pneumoniae in Russia: results of a prospective multicenter study (phase A of the PeGAS-1 project) // Clinical microbiology and antimicrobial chemotherapy. 2002; 3: 267-77. 7. PROTEKT Study Database. Feb. 2001 (http:https://wwwprotekt.org). 8. Oskina E.A. Optimization of antimicrobial chemotherapy in patients of older age groups in a geriatric hospital. Author's abstract. Diss. for an academic degree of M.Sc. Samara. 2006; 24.

Adverse reactions of macrolide antibiotics

Unlike other classes of antimicrobial drugs, adverse reactions during the period of taking antibiotics belonging to the macrolide group are quite rare. These drugs are generally easily tolerated by patients, including children, pregnant women and the elderly.

Below is a list of possible reactions during a course of antibacterial therapy with drugs from the macrolide group:

1. From the gastrointestinal tract: abdominal discomfort, pain, nausea, vomiting, diarrhea, which can be caused by erythromycin, as it can have a prokinetic effect, stimulating intestinal motility. Less commonly, similar phenomena are observed when spiramycin and josamycin are prescribed.
2. Adverse events from the liver are most typical for erythromycin. According to research, liver damage during macrolide therapy is 3.6 cases per 100 thousand, so in general, the course of antibacterial therapy is considered favorable. General malaise, weakness, abdominal pain, rarely fever, signs of jaundice are a consequence of cholestatic hepatitis. In this case, ALT and AST are observed. It is important to note that the risk of developing hepatotoxic reactions most often occurs due to the interaction of macrolides with other drugs; a very important indicator in this case is the presence of liver diseases.
3. From the central nervous system, dizziness, headache, and very rarely hearing loss (with intravenous administration of macrolides in extremely high doses) are possible.
4. From the cardiovascular system, changes may appear on the ECG - prolongation of the QT interval.
5. Local reactions caused by intravenous use of macrolide antibiotics include the following: phlebitis and thrombophlebitis. It is important to take into account here that these drugs can only be administered dropwise; jet administration is contraindicated.

Allergic reactions, skin rash, and urticaria are not typical for macrolides and occur in very rare cases.

Indications for prescribing macrolide antibiotics

A course of antibacterial therapy with macrolide drugs is prescribed to patients with various infectious diseases:

1. For upper respiratory tract infections: acute sinusitis, streptococcal tonsillitis, acute otitis media in children (the highest activity is observed with azithromycin, which is also prescribed for allergic reactions to penicillin). Separately, we should dwell on such a disease as streptococcal tonsillopharyngitis - drugs of the macrolide group in this case act as an alternative to penicillin, not being inferior to it in the effectiveness of suppressing the source of inflammation, so they can be prescribed to patients to prevent serious complications of tonsillopharyngitis (rheumatism and glomerulonephritis).
2. For lower respiratory tract infections: chronic bronchitis in the acute stage, community-acquired pneumonia, including those caused by atypical pathogens.
3. For “childhood infections”: whooping cough and diphtheria. In the latter case, erythromycin is prescribed, which is combined with anti-diphtheria serum.
4. For infectious diseases of the skin and soft tissues: furunculosis, moderate and severe forms of skin acne (erythromycin or azithromycin is used), etc.
5. For sexually transmitted infections, both in women and men: syphilis, chlamydia, ureaplasmosis, mycoplasmosis, chancroid, lymphogranuloma venereum.
6. For infections of the oral cavity that affect the tissues surrounding the roots of the teeth - periodontitis, periostitis.
7. Erythromycin is indicated for the treatment of campylobacter gastroenteritis, manifested by diarrhea, nausea, fever and abdominal pain.
8. In the treatment of gastric and duodenal ulcers for the eradication of Helicobacter pylori, the administration of clarithromycin as part of a three- or four-component regimen is indicated.
9. In the treatment of parasitic diseases of humans and animals: spiramycin, a natural antibiotic of the macrolide group, is most often used for the treatment of toxoplasmosis. For cryptosporidiosis, preference is given to spiramycin and roxithromycin.
10. For the prevention and treatment of diseases such as mycobacteriosis caused by mycobacteria M.avium in patients with acquired immunodeficiency syndrome. The most effective drugs in this case should be clarithromycin and azithromycin.
11. For the purpose of prophylactic use, drugs from the macrolide group are prescribed:

• people who have had contact with patients with whooping cough are prescribed erythromycin;
• for patients suffering from rheumatism who have an allergic reaction to penicillin, erythromycin is recommended as an alternative;
• for meningococcal carriage, spiramycin is recommended;
• in dentistry - azithromycin and clarithromycin;
• When performing intestinal decontamination in patients who are being prepared for colon surgery, erythromycin is prescribed in combination with kanamycin.

Modern macrolides in the treatment of community-acquired pneumonia

Pneumonia is a group of acute infectious (mainly bacterial) diseases of different etiology, pathogenesis and morphology, characterized by focal damage to the respiratory parts of the lungs with intra-alveolar exudation, detected during physical and x-ray examinations, as well as feverish reaction and intoxication expressed to varying degrees (Russian Respiratory Society, 2010). According to the Central Research Institute for Organization and Informatization of Healthcare of the Ministry of Health of the Russian Federation, 424,457 people suffered from pneumonia in 2008, and in 2009 - 449,673 patients [1, 2]. The incidence rate of pneumonia is significantly higher in elderly patients and ranges from 25 to 114 per 1000 people per year [3].

Pneumonia ranks first among the causes of mortality from infectious diseases and sixth among all causes of mortality [4]. The most common deaths are observed in cases of severe pneumonia, especially in socially disadvantaged individuals or in patients with severe comorbidities [5, 6].

The following types of pneumonia are distinguished:

• community-acquired pneumonia (home, outpatient) is an acute disease that arose in a community setting, i.e., outside the hospital, diagnosed in the first 48 hours from hospitalization [7];
• nosocomial pneumonia (hospital, nosocomial) - a disease characterized by the appearance on an x-ray of “fresh” focally infiltrative changes in the lungs and clinical data confirming their infectious nature (a new wave of fever, purulent sputum or purulent discharge of the tracheobronchial tree, leukocytosis, etc.) later 48 hours or more after hospitalization [8];
• aspiration pneumonia (with epilepsy, swallowing disorders, vomiting) - pulmonary lesions resulting from aspiration (microaspiration) of a larger or smaller amount of contaminated contents of the nasopharynx, oral cavity or stomach and the subsequent development of an infectious process [9];
• pneumonia in persons with severe immune defects (congenital immunodeficiency, HIV infection, drug addiction, chronic alcohol intoxication, malignant neoplasms, agranulocytosis, use of immunosuppressive therapy).

Community-acquired pneumonia is the largest group, characterized by a severe course and a high risk of complications, including pleurisy, abscesses and other purulent-destructive processes [10].

All community-acquired pneumonia are divided into the following groups:

• pneumonia that does not require hospitalization;
• pneumonia requiring hospitalization;
• pneumonia requiring hospitalization in intensive care units [11].

Risk factors for the unfavorable course of community-acquired pneumonia are:

1. Age over 60 years.

2. Concomitant diseases:

• chronic obstructive pulmonary disease (COPD);
• bronchiectasis;
• malignant neoplasms;
• diabetes mellitus (DM);
• chronic renal failure;
• congestive heart failure;
• chronic alcohol intoxication (CAI);
• addiction;
• severe body weight deficiency;
• past cerebrovascular diseases.

3. Ineffectiveness of initial antibiotic therapy.

Urgent hospitalization in intensive care units is required in cases where the patient has signs of severe community-acquired pneumonia, which include:

• respiratory rate more than 30 per minute;
• systolic blood pressure (SBP) below 90 mm Hg. Art.;
• the presence of bilateral or multilobar pneumonic infiltration;
• rapid progression of focal infiltrative changes in the lungs;
• septic shock;
• the need to administer vasopressors;
• acute renal failure.

It is known that in community-acquired pneumonia, the main pathogen is pneumococcus (Streptococcus pneumoniae) [12], the second most important pathogen is Haemophilus influenzae [13].

In addition to mandatory laboratory and instrumental studies, various PSI and CURB-65/CRB-65 scales are currently used in the diagnosis of community-acquired pneumonia [14].

In order to determine the risk factors, prevalence, structure and frequency of deaths due to pneumonia in a multidisciplinary emergency hospital, the authors conducted a retrospective study, during which 180,727 inpatient records were analyzed. Of these, 172,420 patients (95.5%) were treated and discharged, 1677 (0.9%) patients were transferred to other health care facilities, and 6630 patients (3.6%) died.

Of the deaths, the study included 1497 cases of community-acquired pneumonia confirmed at the section, which were divided by the authors into two subgroups: “Community-acquired pneumonia as the main disease” (I) included 97 patients (6.4%) and “Community-acquired pneumonia as a complication of the main disease "(II) included 1400 (93.6%) patients (Fig. 1).

Among the 1497 deceased patients with community-acquired pneumonia, there were 768 men (51.4%) and 729 women (48.6%) (Fig. 2).

The age structure of 1497 patients with community-acquired pneumonia is presented in Fig. 3. As can be seen from this illustration, the majority of patients (43%) were over 75 years of age.

Of the 1497 cases of community-acquired pneumonia that resulted in death, in 136 observations (9%) there was a discrepancy between the clinical and pathological diagnoses (Fig. 4).

According to the nature of the lesion, pleuropneumonia occurred in 49.4% of cases, focal confluent pneumonia - in 22.6%, abscess pneumonia - in 19.5%, and focal pneumonia - in 8.5% of cases.

By localization, bilateral community-acquired pneumonia was more common - 41 (42.2%). A summary table of the locations of pulmonary tissue damage in community-acquired pneumonia is presented below (Table 1).

Community-acquired pneumonia was combined with CAI in 71.1% of cases, with previous stroke in 56% of cases, with COPD in 24.7% of cases, with multifocal atherosclerosis in 32% of cases, with ischemic disease in 25.7% of cases heart disease (CHD), in 20.6% of events - with type 2 diabetes (Fig. 5).

Thus, in the vast majority of observations, community-acquired pneumonia is secondary, i.e., it is a complication of the main or background disease, aggravates its course and worsens the prognosis of patients. The data obtained by the authors in case of suspected pneumonia dictate the need for a diagnostic search aimed at identifying the substrate for the development of the inflammatory process in the lung tissue. In this regard, diagnosis, and often treatment of community-acquired pneumonia remains one of the pressing problems of modern therapy. The choice of antibiotic for the treatment of pneumonia is usually done empirically. In this case, the guidelines for its choice are the epidemiological situation, the expected sensitivity of the flora (Table 2) and some other aggravating factors [15].

The semisynthetic macrolide clarithromycin, along with aminopenicillins and respiratory fluoroquinolones, occupies one of the leading positions in the treatment of community-acquired pneumonia and other infectious diseases of the lower respiratory tract. The multifaceted etiopathogenetic effect of clarithromycin on the process of bacterial inflammation ensures its high effectiveness, confirmed in a number of comparative studies. The antimicrobial spectrum of clarithromycin, including S. pneumonia, H. influenza, as well as new prolonged forms of the drug, determines its demand in the treatment of this category of patients. In the presence of atypical mycobacteria and Pseudomonas aeruginosa, clarithromycin is used in combination with other antimicrobial drugs, significantly increasing the effectiveness of the therapy.

The mechanism of the antimicrobial action of clarithromycin is due to a violation of protein synthesis in the microbial cell. As a result of reversible binding to the 50 S-subunit of ribosomes and inhibition of translocation and transpeptidation reactions, the formation and growth of the peptide chain is inhibited [16]. The main effect of clarithromycin is bacteriostatic, but at high concentrations and low microbial density the drug has a bactericidal effect against S. pyogenes and S. pneumoniae. Moreover, the antimicrobial activity against these pathogens and methicillin-sensitive strains of Staphylococcus aureus is 2–4 times higher than that of erythromycin [17].

Many clinical studies and as a result of many years of experience in use have revealed the high effectiveness of clarithromycin in the treatment of lower respiratory tract infections. According to the results of a study that included 252 patients with community-acquired pneumonia, a 7-day course of treatment with extended-release clarithromycin (1000 mg once daily) was as clinically effective as a similar duration of treatment with levofloxacin (500 mg once daily). The overall rates of pathogen eradication (87% and 88%, respectively) and radiographic improvement (95% and 88%, respectively) also did not differ. Both drugs turned out to be equally effective against both typical and atypical pathogens [18].

In severe cases of community-acquired pneumonia in a hospital setting, combination therapy is more effective. This has been confirmed by many clinical observations. A cohort study involving 1391 patients with community-acquired pneumonia found that mortality during treatment with a combination of a third-generation cephalosporin with a macrolide was 2 times lower than with beta-lactam monotherapy [19]. Another study showed that the combination of a beta-lactam with a macrolide is more effective than that of a beta-lactam with a fluoroquinolone (mortality rate - 4.9% and 15.0%, respectively) [20].

Regardless of the antimicrobial effect, clarithromycin, like a number of other macrolides, exhibits anti-inflammatory, immunomodulatory and mucoregulatory effects at the level of the respiratory system. Clarithromycin has a modulating effect on phagocytosis, chemotaxis, killing and apoptosis of neutrophils. The oxidative “explosion” is inhibited, resulting in a decrease in the formation of highly active compounds that can damage one’s own tissues. The synthesis and/or secretion of pro-inflammatory cytokines (interleukins-1, 6, 8, tumor necrosis factor alpha) is inhibited and the secretion of anti-inflammatory cytokines (interleukins-2, 4, 10) is enhanced [21].

Thus, the presence of additional properties, along with high antibacterial activity, ensures rapid regression of symptoms and improvement in the condition of patients when treated with clarithromycin for respiratory tract infections.

Clarithromycin has rightfully occupied its niche in the treatment of acute and chronic respiratory tract infections. It retains one of the leading positions in outpatient practice and in the pharmaceutical market of the Russian Federation, which is due to its wide spectrum of activity, rapid achievement of high peak concentrations at the site of infection and a favorable safety profile. A dosage form with a delayed release of the active substance due to a special surface layer and matrix base (Klacid SR) is identical in effectiveness to the standard one, is better tolerated, improves compliance and can be recommended for active use. The evidence available today on non-antibacterial action, combined with the favorable clinical and pharmacological characteristics of clarithromycin, allows us to consider it as an adjuvant drug in the treatment of many respiratory diseases.

Literature

1. Morbidity rate of the Russian population in 2007. Statistical materials of the Ministry of Health and Social Development of Russia, 2008, 527–572.
2. Community-acquired pneumonia in adults. Clinical recommendations (edited by A. G. Chuchalin, A. I. Sinopalnikov). M.: Atmosphere, 2005.
3. Zilber A.P. Sketches of respiratory medicine. M.: Medpress-inform, 2007.
4. Ewig S. Community-acquired pneumonia. Epidemiology, risk, and prognosis // Eur Respir Mon. 1997; 3: 13–35.
5. Mira JP., Max A., Burgel P.-R. The role of biomarkers in community-acquired pneumonia: predicting mortality and response to adjunctive therapy // Critical Care. 2008; 12(Suppl. 6):S5 1–7.
6. Rodriguez R., Fancher M., Phelps M. An emergency department based randomized trial of nonbronchoscopic bronchoalveolar lavage for early pathogen identification in severe community-acquired pneumonia // Ann Emerg Med. 2001; 38: 357–363.
7. Vardakas KZ, Siempo II, Grammatikos A. Respiratory fluoroquinolones for the treatment of community-acquired pneumonia: a meta-analysis of randomized controlled trials // CMAJ. 2008; 179(12):1269–1277.
8. Drummond MF, Becker DL, Hux M. An economic evaluation of sequential iv/po moxifloxacin therapy compared to iv/po coamoxiclav with or without clarithromycin in the treatment of community-acquired pneumonia // Chest. 2003; 124:526–535.
9. Landen H., Moller M., Tillotson GS Clinical experience in Germany of treating community-acquired respiratory infections with the new 8-methoxyfluoroquinolone, moxifloxacin // J Int Med Res. 2001; 29:51–60.
10. Li X., Zhao X., Drlica K. Selection of Streptococcus pneumoniae having reduced susceptibility to levofloxacin and moxifloxacin // Antimicrob Agents Chemoter. 2002; 46:522–524.
11. Marrie TJ, Peeling RW, Fine MJ Ambulatory patients with community-acquired pneumoniae: the frequency of atypical agents and clinical course // Am J Med. 1996; 101:508–515.
12. Sethi S. The role of antibiotics in acute exacerbation of COPD // Curr Infect Dis Rep. 2003; (5): 9–15.
13. Torres A., Muir J.-F., Corris P. Effectiveness of oral moxifloxacin in standard first-line therapy in community-acquired pneumonia // Eur Respir J. 2003; 21: 135–143.
14. Wilson W. Short-term and long-term outcomes of moxifloxacin compared to standard antimicrobic treatment in acute exacerbation of chronic bronchitis // Chest. 2004; 125:(3):953–964.
15. Bartlett JG, Dowell SF, Mandell LA Practice guidelines for the management of community-acquired pneumonia in adults. Infectious Diseases Society of America // Clin Infect Dis. 2000; 31: 347–382.
16. Wozniak DJ, Keyser R. Effects of subinhibitory concentrations of macrolide antibiotics on Pseudomonas aeruginosa // Chest. 2004; 125: 62 S-9 S.
17. Sivapalasingam S., Steigbigel NH Macrolides, clindamycin, and ketolides. Pronciples & Practice of Infectious Diseases // Churchill Livingstone, 6th edition. 2004: 396–417.
18. Kozlov RS, Sivaja OV, Stratchounski LS 7-year monitoring of resistance of clinical S. pneumoniae in Russia: results of prospective multicenter study (PEHASus) // Proc 45th ICAAC, 2005, Washington DC.
19. Stahl JE, Barza M., DesJaidin J. Effect of macrolides as part of initial empiric therapy on length of stay in patients hospitalized with community-acquired pneumonia // Arch Intern Med. 1999; 159:2576–2580.
20. Martinez JA, Horcajada JP, Almela M. Addition of a macrolide to a beta-lactam-based empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia // Clin Infect Dis. 2003; 36:389–395.
21. Martinot JB, Carr WD, Cullen S. Clarithromycin Once-a-Day Study Group. A comparative study of clarithromycin modified release and amoxicillin/clavulanic acid in the treatment of acute exacerbation of chronic bronchitis // Adv Ther. 2001; 18:1–11.

A. L. Vertkin, Doctor of Medical Sciences, Professor Zh. M. Oralbekova A. S. Skotnikov, Candidate of Medical Sciences

GBOU VPO MGMSU Ministry of Health and Social Development of Russia , Moscow

Contact information for authors for correspondence

Contraindications to the use of macrolides

Allergy to the corresponding drug should be considered a contraindication when prescribing macrolide antibiotics; pregnancy (this contraindication is relevant to clarithromycin, midecamycin or roxithromycin); During breastfeeding, the above antibiotics, as well as spiramycin and josamycin, are contraindicated.

Warnings

• During pregnancy, the use of clarithromycin should be avoided, as there is evidence of its negative effects on fetal development. At the moment, there is no information that could confirm the absence of negative effects of roxithromycin and midecamycin, as a result of which their use during pregnancy should be avoided.
• Macrolide antibiotics such as josamycin, spiramycin and erythromycin do not cause negative effects on the fetus. Therefore, a course of antibacterial therapy with these drugs is not contraindicated for pregnant women.
• Azithromycin can be recommended with caution during pregnancy.
• During breastfeeding, antibiotics pass into breast milk, so only erythromycin is safe for a nursing woman. These data are not available for azithromycin, and all other macrolide antibiotics are contraindicated for nursing women. During treatment with macrolides, breastfeeding should be suspended.
• For children, macrolides are prescribed from 6 months in a special children's form. For example, Ecomed (azithromycin) is available in powder form for the preparation of a suspension, which makes its use in children convenient.
• Prescribing antibacterial therapy with macrolides to older people does not pose any danger. However, when prescribing erythromycin, it is necessary to take into account its possible negative effect on hearing.
• If renal function is impaired, T1/2 of clarithromycin can be increased to 20 hours (if creatine clearance decreases to less than 30 ml/min), and the half-life of its active metabolite is extended to 40 hours.
• T1/2 of roxithromycin when creatine clearance decreases to 10 ml/min increases to 13-15 hours. In this regard, in case of renal failure, titration of the dose of these macrolide antibiotics is required.
• in case of severe liver dysfunction, treatment with antibiotics of this group should be avoided, since the elimination time of the drug increases, which can lead to an increased risk of hepatoxicity. Of particular note is the occurrence of such adverse events when using josamycin and erythromycin.
• Given the possible effect on prolongation of the QT interval, caution should be exercised when treating macrolide antibiotics in patients suffering from heart disease. An electrocardiogram allows you to see changes in the functioning of the heart.

The use of macrolides in children in modern conditions

Through chemical and microbiological transformation, so-called semi-synthetic antibiotics have been created that have new, medically valuable properties: acid and enzyme resistance, an expanded spectrum of antimicrobial action, better distribution in tissues and body fluids, and fewer side effects. Based on the type of antimicrobial action, antibiotics are divided into bacteriostatic and bactericidal, which is of practical importance when choosing the most effective therapy. A comparative analysis of antibiotics is based on indicators of their effectiveness and safety, determined by the severity of the antimicrobial effect in the body, the rate of development of resistance of microorganisms during treatment, the absence of cross-resistance in relation to other chemotherapy drugs, the degree of penetration into lesions, the creation of therapeutic concentrations in the patient’s tissues and fluids, and the duration of their maintenance, the preservation of action in various environmental conditions. Important properties are also stability during storage, ease of use with different methods of administration, high chemotherapeutic index, absence or mild toxic side effects, as well as allergization of the patient. A discussion of the place of antibiotics in the treatment of bacterial infections in childhood cannot be complete without addressing the problem of antimicrobial resistance. Due to the repeated and often unjustified prescription of antibiotics, the incidence of infections caused by microorganisms that have become resistant to the antibiotics used is increasing throughout the world. The growth in the number of patients with immunodeficiency, the introduction of new invasive medical techniques, mutations of the microorganisms themselves, and some others also play a role in the formation of resistance. Antibiotic resistance is currently leading to increased morbidity, mortality and healthcare costs worldwide. Due to the rapid increase in resistance, problems arise especially acutely in the treatment of bacterial infections in childhood. Of particular importance is the resistance to penicillin and cephalosporin of Streptococcus pneumoniae, the multidrug resistance of Haemophilus influenzae (insensitive to ampicillin, chloramphenicol, tetracycline and trimethoprim), the rapid spread of penicillin-resistant Neisseria meningitidis. Methicycline-resistant strains of Staphylococcus aureus are increasingly being discovered; All over the world, doctors are faced with multidrug resistance in Enterobacteriaceae (thus, the number of isolated cultures of Klebsiella and Enterobacter species that are insensitive to third-generation cephalosporins is increasing). Resistance of Salmonella and Shigella species is developing, in particular, to trimethoprim and cephalosporins, enterococci to vancomycin, and group A streptococci to erythromycin. Although the emergence of antibiotic resistance may be an inevitable result of widespread use, the problem of resistance can certainly be reduced in practice. For example, in Holland the use of systemic antibiotics is limited by the state program and the problem of resistance is not so acute. In recent years, many new antibiotics of different pharmacological groups have been introduced into medical practice. However, the group of macrolides currently attracting the greatest attention from clinicians. This is facilitated by the increasing frequency of drug allergies to penicillins and cephalosporins in the pediatric population, as well as the ineffectiveness of b-lactams for infections caused by intracellular pathogens. Macrolides are now one of the most rapidly developing classes of antibiotics due to their high efficiency and relative safety. They have a wide spectrum of antimicrobial activity and favorable pharmacokinetic properties, combine high efficiency in the treatment of infections and good tolerance by patients. The first macrolide antibiotic synthesized in 1952 was erythromycin, obtained by Waksman from the soil fungus Streptomyces erythreus. Three years later, two more macrolide drugs appeared - spiramycin and oleandomycin. For a long time, erythromycin remained the only alternative in the treatment of many bacterial infections in children allergic to b-lactams. In recent years, a real scientific breakthrough has occurred: several, in a certain sense, unique in their qualities, drugs have been created that hold a “high bar” to this day: azithromycin (Zithrocin, etc.), roxithromycin, clarithromycin, spiramycin, etc. Macrolides got their name due to the presence of a macrocyclic lactone core. Depending on the number of carbon atoms in the lactone ring, macrolides are divided into 3 subgroups: • 14-membered (erythromycin, oleandomycin, roxithromycin, clarithromycin); • 15-membered (azithromycin); • 16-membered (spiramycin, josamycin, midecamycin). One of the general properties of macrolides is a bacteriostatic effect, which is caused by disruption of protein synthesis in the microbial cell through reversible binding to the 50S ribosomal subunit. The bacteriostatic effect in this case has its own characteristics. On the one hand, the microbial agent is not completely destroyed, but on the other hand, there is no effect of additional intoxication of the body due to the action of toxins released from the destroyed microbial cell. When high concentrations of the antibiotic accumulate at the site of infection, macrolides have a so-called post-antibiotic effect, which means suppression of bacterial activity when the effect of the drug has theoretically ceased. The mechanism of this effect is not fully understood. Macrolides are weak bases, their antimicrobial activity increases in an alkaline environment. At pH 5.5–8.5, they penetrate more easily into the microbial cell and are less ionized. Macrolides are metabolized in the liver, and, as a rule, more active metabolites are formed. The main route of elimination is through the gastrointestinal tract (about 2/3 of the drug), the remaining amount is excreted through the kidneys and lungs, so dose adjustment of macrolides is required only in cases of severe liver failure. 14-member macrolides have an important additional property: they exhibit an anti-inflammatory effect by increasing the production of endogenous glucocorticoids and changing the cytokine profile due to activation of the hypothalamic-pituitary-adrenal system. In addition, the stimulating effect of macrolides on neutrophil phagocytosis and killing has been established. Food has a multidirectional effect on the bioavailability of macrolides: it does not affect the absorption of telithromycin, clarithromycin, josamycin and midecamycin acetate; slightly reduces the bioavailability of midecamycin, azithromycin and significantly reduces the bioavailability of erythromycin and spiramycin. Concomitant use with lipid-rich food increases the bioavailability of the tablet form of azithromycin. The pharmacokinetics of macrolides is characterized by a pronounced dependence on the pH of the environment, when it decreases, ionization at the site of inflammation increases and part of the drug is converted into inactive forms. The optimal effect of erythromycin, clarithromycin and especially azithromycin occurs at pH>7.5. Macrolides penetrate well into the cells of the human body, where they create high concentrations, which is fundamentally important for the treatment of infectious diseases caused by intracellular pathogens (Mycoplasma spp., Chlamydia spp., Legionella spp., Campylobacter spp.). With the exception of roxithromycin, the content of macrolides in monocytes, macrophages, fibroblasts and polymorphonuclear leukocytes is tens, and for azithromycin hundreds of times higher than their serum concentration. An important feature of macrolides is their ability to accumulate in phagocytes with subsequent release at the site of infection under the influence of bacterial stimuli and the active recapture of the drug “not utilized” by microorganisms. The maximum accumulation of macrolides is observed in lung tissue, fluid lining the mucous membranes of the bronchi and alveoli, bronchial secretions, saliva, tonsils, middle ear, sinuses, gastrointestinal mucosa, prostate gland, conjunctiva and eye tissues, skin, bile, urethra, uterus, appendages and placenta. Metabolism of macrolides is carried out in the liver by enzymes of the cytochrome P450 system. According to the degree of affinity for enzymes, all macrolides can be divided into three groups: a) oleandomycin and erythromycin have the greatest affinity; b) clarithromycin, midecamycin, josamycin and roxithromycin are characterized by weak affinity; c) when using azithromycin, dirithromycin and spiramycin, competitive binding with enzymes does not occur. The half-life (T1/2) differs for different macrolides and may depend on the dose: azithromycin has the longest T1/2 - up to 96 hours, the shortest - erythromycin and josamycin - 1.5 hours (Table 1). Macrolides are excreted from the body mainly with bile, undergoing enterohepatic recirculation. In addition to the direct antimicrobial effect on the cell, some macrolides are distinguished by properties that enhance their effectiveness in the conditions of the macroorganism. Among them: •? post-antibiotic effect, which manifests itself in the absence of the effect of resumption of bacterial growth, despite the removal of the antibiotic from the body. •? subinhibitory effect, but it is difficult to use in therapeutic regimens, since the use of antibiotics in subinhibitory concentrations may cause an increase in resistance to it. It is used as a test to assess the distribution of a bacterial population according to the degree of antibiotic sensitivity and the proportion of resistant individuals in it, a high number of which may indicate signs of the formation of resistance. Macrolides are an undisputed alternative in case of allergy to b-lactams in the treatment of tonsillitis, sinusitis, otitis, bronchitis, pneumonia, skin and soft tissue infections (Table 1). Considering that macrolides have an equally good effect on both extracellular and intracellular pathogens, they have become first-line antibiotics in the treatment of many urogenital infections and so-called atypical bronchopulmonary infections caused by chlamydia, mycoplasma, etc. Macrolides are also used in gastroenterology and are increasingly included in treatment regimens for chronic gastroduodenitis associated with H. pylori (for example, clarithromycin). Macrolides are first-line antibiotics in the treatment of whooping cough in children (moderate and severe forms), and are included in the complex of therapeutic measures for diphtheria of the pharynx. Resistance to macrolides does not yet pose serious problems in most regions of Russia, as evidenced by the results of the multicenter study PeGAS-I. According to the data presented, the prevalence of resistant clinical strains of S. pneumoniae is within 4%. Modern macrolides have convenient release forms: from tablets with different dosages to suspensions and syrups, which can be prescribed to children even at an early age. Some macrolides are available in the form of ointments for external use (erythromycin), and also have forms for parenteral administration (erythromycin, clarithromycin, azithromycin), which makes their use possible in emergency situations. All new macrolides are significantly superior in their pharmacological properties to both erythromycin and midecamycin, have a more prolonged effect, are designed to be taken 1-2 times a day, and have significantly fewer side effects. But in other qualities these drugs have differences, sometimes significant. The absorption of azithromycin depends on the timing of meals. Bioavailability is considered to be greatest for roxithromycin (72–85%) and clarithromycin (52–55%) compared to azithromycin (37%), spiramycin (35%), etc. From the 50s of the last century to the present day, macrolides have been used with high efficiency, especially for pathologies of the upper respiratory tract. In terms of frequency of use, macrolides occupy third place among all classes of antibiotics, and in the treatment of tonsillitis they compete with penicillins. According to T.I. Garashchenko and M.R. Bogomilsky [3], this is due to a number of reasons: 1. High degree of accumulation of macrolides in lymphoid tissue. 2. Efficiency (up to 90%) in patients with tonsillopharyngitis. 3. Increased frequency of isolation from the tonsils (especially with recurrent tonsillopharyngitis) of microorganisms producing b-lactamases capable of destroying penicillins, first generation cephalosporins (M. catarrhalis, St. aureus) and high activity of macrolides against these pathogens. 4. An increase in the frequency of atypical pathogens (M. pneumoniae, CI. pneumoniae) in the etiology of acute and recurrent tonsillopharyngitis, adenoids (up to 43%), inaccessible to penicillins (including protected ones), cephalosporins, aminoglycosides, lincosamides. 5. Few side effects compared to other antibiotics. 6. No effect on the microflora of the intestines and pharynx, moderate antifungal effect. 7. High safety range, allowing the dose of macrolide (azithromycin) to be doubled to achieve a bactericidal effect. 8. High compliance due to short courses of treatment (3–5 days for azithromycin) and ease of administration of the drug (once a day for azithromycin). 9. Activity of some macrolides against H. influenzae (azithromycin). 10. The absence of competitive interaction between azalides and antifungal and antihistamine drugs, which allows for combination therapy in children with allergic manifestations and mycoses. 11. High activity of macrolides not only against nonspecific pathogens of pharyngeal diseases (GABHS, St. aureus, Str. pneumonia), but also specific ones - N. meningitides, N. gonorrhoeas, Treponema pallidum, Legionella pneumonia, Lisferia monocytogenes, Coryne-bacterium diphtheriae, activity against anaerobes - causative agents of paratonsillitis. 12. Immunomodulatory effect. Despite the large number of positive criteria, in the last few years there has been some caution regarding the use of macrolide antibiotics due to reports of an increase in resistance to them in vitro in a number of countries (France, Italy, Spain), which, however, is not accompanied by reports of corresponding this increase in clinical ineffectiveness of macrolide antibiotics. Moreover, the high safety of macrolide antibiotics, and primarily azithromycin, allows the use of new dosage regimens (treatment of acute otitis media with a single dose) and their improvement to achieve a better bactericidal effect in patients with a burdened premorbid background. Thus, R. Cohen [cit. according to 4], analyzing the clinical and bacteriological effectiveness of treatment of chronic tonsillitis with azithromycin at a course dose of 30 and 60 mg/kg, taken for 3 days, notes that bacteriological effectiveness at a dose of 30 mg/kg was registered only in 58% of cases, whereas with 60 mg/kg – achieved 100% bacteriological eradication of the pathogen, comparable to a 10-day course of penicillin (95%). The cost of macrolides in the modern pharmaceutical market varies widely: from expensive original drugs, undoubtedly of higher quality, to more affordable generics, some of which are also of good quality (zitrocin, clerimed, roxihexal, etc.), which ensures accessibility drugs of this group to all segments of the population. But the doctor should not only be guided by the price of the drug when prescribing treatment for a child. An analysis of the clinical effectiveness of various representatives of macrolides shows that the unreasonable and frequent prescription of a popular drug in one region throughout the year can negate the antimicrobial effect, since under these conditions protoplasts and L-forms are quickly formed. Macrolides are well tolerated and can be successfully used in children from birth. However, this does not apply to clarithromycin and azithromycin suspension, the safety and effectiveness of which have not been studied in children under 6 months of age. Doses of macrolides used in children are presented in Table 2. Adverse reactions requiring discontinuation of the drug: allergic reactions - anaphylaxis and Quincke's edema (extremely rare); acute cholestatic hepatitis; cardiotoxic effect (prolongation of the QT interval, arrhythmias); pseudomembranous colitis; acute interstitial nephritis; reversible hearing loss. Adverse reactions that require attention if they persist for a long time and/or are poorly tolerated: allergic reactions (urticaria, itchy skin); pain at the injection site; reactions from the gastrointestinal tract (nausea, vomiting, changes in taste, pain and discomfort in the abdomen, diarrhea); dizziness and headache (extremely rare). The most typical adverse reactions are observed in the gastrointestinal tract. In the case of azithromycin and clarithromycin, their frequency rarely reaches 12%, but when using erythromycin base it can increase to 32%. With the use of josamycin, clarithromycin, spiramycin and high doses of erythromycin (? 4 mg/day), acute cholestatic hepatitis is possible. When prescribing high doses of erythromycin in terms of 36 hours to 8 days, a reversible hearing loss is possible. High doses of erythromycin, teelithromycin and spiramycin can cause extension of the QT interval and the occurrence of ventricular tachycardia such as “Torsades de Pointes”. Cross allergic reactions to all macrolides are extremely rare. Although macrolides can contribute to a change in the intestinal biocenosis, this acquires clinical value in very rare cases with the development of Clostridium dificille - ascified pseudo -dummy colitis, diarrhea, vaginal or oral candidiasis. Among the macrolide drugs, a special place is occupied by azithromycin, obtained and implemented in clinical practice in the early 90s of the XX century. This is the first representative of the new subgroup of antibiotics - azalids, in the structure of the lacton ring of which a nitrogen atom is contained. Such a restructuring of the erythromycin molecule gave the obtained compound new properties, including the expansion of the antimicrobial spectrum, the creation of high levels in tissues and cells significantly exceeding the concentration in the blood (tissue orientation of pharmacokinetics), and other properties that significantly distinguish it from the antibiotics of the macrolides group. Along with maintaining activity against gram -positive cocci of azithromycin (zyspin and others), it exceeds erythromycin against Haemophilus influenzae, Moraxella Catarrhalis, Neisseria spp., Campylobacler jejuni, Helicobacter pylori, Borrelia Burgdorferi. It is also active in relation to some enterobacteria: its value of the MPK90 in relation to Salmonella, SHIGELLA, E.Coli ranges from 4–16 mg/l. Azithromycin (zysprine and others) is active in relation to some “atypical” microorganisms, as well as intracellularly located pathogens - Chlamydia spp., Mycoplasma spp. and others. Azithromycin at various pH values ​​is more stable than erythromycin. After taking a single dose in the stomach, more than 37% of azithromycin is absorbed compared to 25% of erythromycin. Food or simultaneous use of antacids reduces the bioavailability of azithromycin, and therefore it should be taken at least 1 hour before or 2 hours after eating. The concentration of azithromycin in tissues and cells exceeds 10-100 times detected in the blood; The intracellularly concentrates in the lysosomes. The average value of T1/2 of azithromycin is 2-4 days. In the recommended treatment conditions (3 and 5 days), the drug in effective concentrations is maintained within 7 or more days. When resolving the issue of repeated courses of antibacterial therapy, it is necessary to take into account the properties of azithromycin into the body's tissues, which allows reducing the duration of the course of treatment with azithromycin and provides a stagiotic effect. Azithromycin quickly includes in white blood cells (polynuclear, monocytes, lymphocytes), in high concentrations and is detected for a long time in alveolar macrophages, fibroblasts. During migration into the focus of infection, polynuclera plays a transport role, providing a high and long -lasting antibiotic level in tissues and cells. Even with the introduction of azithromycin in maximum doses, it creates low concentrations in the blood, but has high penetration into polynuclear (phagocytes), responsible for the clearance of pathogens from the focus of infection and blood channel. The drug is not metabolized in the patient’s body, does not inhibit the isoenzymes of the p450 cytochrome system. From the patient’s body is excreted mainly with feces and partially (~ 20%) in urine. Thus, modern synthetic macrolides (azithromycin, clarithromycin, roxytromycin) are characterized by a wide range of action: they are active against most gram -positive microorganisms, many gram -negative bacteria, “atypical” intracellular pathogens of respiratory infections; The spectrum of their actions also includes atypical mycobacteria, pathogens of a number of dangerous infectious diseases (rickests, brucelli, borrelia, etc.) and some simplest. They surpass natural macrolides not only in terms of breadth of the spectrum and degree of antibacterial activity, but also in the bactericidal effect on many pathogens. New macrolides (especially azithromycin) have improved pharmacokinetic properties: prolonged with pharmacokinetics (T1/2 of azithromycin, depending on the dose, is 48–60 hours), the ability to accumulate and linger for a long time in immunocompetent cells for 8-12 days after the completion of 3-5 —The day internship courses in a standard dose. The interest of pediatricians in azithromycin is due to its high degree of accumulation in the lymphoid tissue and long -term preserved concentrations of the drug, providing the bactericality of the effect, as well as rare side effects, the lack of effect on the normal microflora of the oral cavity and intestines, and a low probability of drug interaction. The tissue and cell orientation of kinetics, the prolonged effect of new macrolides, the possibility of their effective use in short courses without the risk of developing serious adverse reactions determine the low frequency of antibiotic resistance.

Literature 1. Strachunsky L.S., Kozlov S.N. Macrolides in modern clinical practice. Smolensk: Rusich, 1998. 2. Samsygina G.A., Bogomilsky M.R., Garashchenko T.I. Antibacterial therapy of acute respiratory diseases in children. Lectures on Pediatrics Volume 2. Ed. V.F. Demina, S.O. Klyuchnikova, G.A Samsygina. RGMU. Moscow, 2002 3. Garashenko T.I., Bogomilsky M.R. New approaches to the treatment of exacerbations of chronic tonsillitis in children. // Children's infections, No. 1 - 2004. 4. Lukyanov S.V. Clinical pharmacology of macrolides. Consilium medicum 2004; No. 6, p. 769–73. 5. Mizernitsky Yu.L., Sorokina E.V. Macrolides for respiratory tract infections: modern ideas about the mechanisms of action. Consilium medicum, Pediatrics, 2006; No. 2, c. 23–26.

Information for patients taking macrolide antibiotics

Instructions for the use of antibacterial drugs belonging to the group of macrolides serve as the main guideline in prescribing a course of treatment. This or that drug should be taken as prescribed by the attending physician, taking into account factors such as the presence of chronic diseases, general malaise, reduced immunity, age, pregnancy, breastfeeding and individual characteristics of the body.

The general rules for the use of macrolide antibiotics are as follows:

• Macrolides should be taken orally 1 hour before meals or 2 hours after meals. Exceptions are clarithromycin, spiramycin and josamycin; they can be taken without taking into account meal times; Erythromycin should be taken with plenty of water (at least 1 full glass);
• when preparing suspensions for children, it is recommended to follow the attached instructions;
• You cannot, without a doctor’s recommendation, change the time interval between taking antibiotics, skip or change the dosage (increase or decrease);
• if for some reason the required dose was missed, you should take it as quickly as possible, but if it is already time to take the next one, you should not do this;
• it is necessary to adhere to the prescribed course of therapy and not increase it on your own, do not stop taking the drug prematurely (this is especially important to consider in case of streptococcal infections);
• when treating with erythromycin, it is necessary to abstain from alcohol-containing drinks and medications during treatment;
• You cannot combine the use of macrolides with antacids.

Main characteristics and features of the use of various macrolides

1. Erythromycin - used 2 to 4 times a day. The peculiarities of erythromycin include the fact that when taking the drug orally, it is important to take into account the presence of food - it reduces the bioavailability of the drug. With simultaneous use of erythromycin with theophylline, cisapride, carbamazepine, disopyramide and cyclosparine, an increase in the concentration of the drug in plasma may be observed. When taking erythromycin, adverse events from the gastrointestinal tract often occur. The drug can be used in pregnant and lactating women.
2. Clarithromycin - recommended oral administration 2 times a day; A feature of clarithromycin should be considered its high activity against H. pylori, as well as atypical mycobacteria. Clarithromycin is characterized by higher bioavailability and tissue penetration compared to erythromycin. This macrolide is prescribed with caution for renal failure and is not recommended for use in pregnant and lactating women. In pediatric practice, clarithromycin is used from 6 months. An eco-analogue of clarithromycin is available in tablets under the trade name Ecositrin.
3. Azithromycin is used once a day, as it has a very long half-life. It can accumulate in tissues in significant concentrations, which makes it possible to use azithromycin in short courses (3-5 days). Single use is possible in children with acute otitis media and in adults with acute urogenital chlamydia. Take azithromycin 1 hour before a meal or 2 hours after a meal, since it is advisable to take it on an empty stomach. Azithromycin is more active than other macrolides against Pseudomonas aeruginosa and enterobacteria. An eco-analogue of azithromycin, Ecomed, is available in capsules, tablets and powder for the preparation of a suspension (children's form).
4. Roxithromycin - prescribed 1-2 times a day, regardless of meals. If the patient has renal failure, the standard therapeutic dose should be reduced. Therapy with roxithromycin is easier to tolerate than treatment with erythromycin and is less likely to interact with other drugs. This antibiotic should not be used during pregnancy and breastfeeding.
5. Spiramycin - used 2-3 times a day. Women should interrupt breastfeeding while taking the drug. This macrolide antibiotic has high bioavailability regardless of food intake, and creates higher concentrations of the active substance in tissues than erythromycin. The drug is usually well tolerated by patients, and no interactions with other drugs have been established to date. Spiramycin is active against some streptococci that exhibit resistance to 14- and 15-membered macrolides. Unlike other macrolides, spiramycin can be prescribed for toxoplasmosis and cryptosporidiosis.
6. Josamycin - taken orally 3 times a day; unlike erythromycin, josamycin is rapidly absorbed from the gastrointestinal tract regardless of the presence of food; this macrolide is active against some staphylococci and streptococci resistant to erythromycin; The drug is not prescribed for breastfeeding women.
7. Midecamycin - take 3 times a day, preferably an hour before meals. Therapy with this macrolide antibiotic is well tolerated by patients; no interactions with other drugs have been identified; Contraindicated for lactating and pregnant women.
8. Midecamycin acetate is a derivative of midecamycin, which has higher antibacterial activity and bioavailability; taken 3 times a day, contraindications are similar to midecamycin.

Macrolides

Macrolides
(eng.
macrolides
) are drugs whose molecular structure contains a 14-, 15- or 16-membered lactone ring. Most macrolides are antibiotics. Macrolides are agonists of motilin receptors and therefore, to varying degrees, stimulate the motility of the gastrointestinal tract, exhibiting prokinetic properties.

General characteristics of the group of macrolides

Macrolide antibiotics occupy one of the leading positions in antibacterial therapy for a wide range of diseases. They are the least toxic among antimicrobial agents and are well tolerated by patients. According to their pharmacokinetic characteristics, macrolides are classified as tissue antibiotics. Features of the pharmacokinetics of the most commonly prescribed antibiotics include the ability of macrolides to reach higher concentrations at the site of infection than in the blood plasma. Historically, the first macrolide is the natural antibiotic erythromycin, discovered in 1952, isolated from the streptomycete species Streptomyces erythreus
(later reclassified as the species
Saccharopolyspora erythraea
).

The first semisynthetic macrolide is roxithromycin. The most commonly used macrolide currently used in clinics is clarithromycin. Both erythormycin, roxithromycin, and clarithromycin are antibiotics and have a 14-membered lactone ring in their molecules.

In the group of macrolides, a subgroup of azalides is distinguished, in which a nitrogen atom is additionally included in the lactone ring between the 9th and 10th carbon atoms (the ring thus becomes 15-membered). The most famous azalide is the semisynthetic antibiotic azithromycin.

Of the 16-membered antibiotics, the best known is the naturally occurring antibiotic josamycin.

14-membered macrolides, in which a keto group is attached to the lactone ring at the 3rd carbon atom, are classified as ketolides. Ketolides were developed to combat macrolide-resistant pathogens of respiratory tract infections and have not become widespread in gastroenterology.

Natural macrolide with a 23-membered ring, tacrolimus, first obtained from streptomycetes of the species Streptomyces tsukubaensis

, is an immunosuppressive drug that is not an antibiotic. Due to the inherent quality of macrolides to stimulate the motor-evacuation function of the gastrointestinal tract, tacrolimus is the most effective drug among immunosuppressants in the treatment of gastroparesis that occurs after allogeneic bone marrow transplantation and in other similar situations (Galstyan G.M. et al.).

Macrolide antibiotics are characterized by high bioavailability (30-65%), long half-life (T½), and the ability to easily penetrate tissue (especially azithromycin). Characterized by a direct anti-inflammatory effect. They have a predominantly bacteriostatic effect on gram-positive cocci (streptococci, staphylococci) and intracellular microorganisms (legionella, mycoplasma, chlamydia). Clarithromycin is highly active against Helicobacter pylori

, acid resistance, high concentration in tissues, long half-life (3-7 hours) and good tolerability.
Dose: 500 mg 2 times a day; course of treatment is 7-10 days. Azithromycin is characterized by high bioavailability (40%), high content in tissues, long half-life (up to 55 hours), which allows it to be prescribed once a day and use short courses of treatment (1-5 days); characterized by a long-lasting post-antibiotic effect (5-7 days after discontinuation), good tolerability; active against Helicobacter pylori
. Dose: 500 mg 1 time per day for 3 days (Zimmerman Y.S.).

The use of macrolides in the eradication of Helicobacter pylori

The effectiveness of the use of regimens including macrolides for the eradication of Helicobacter pylori
has been shown in numerous studies.
Macrolides provide the maximum bactericidal effect against Helicobacter pylori
among all antibiotics used in the regimen. This effect is dose-dependent and occurs when using, for example, clarithromycin at a dose of 1000 mg per day. Macrolides also have a significant, pronounced anti-inflammatory effect, which is very important for the correction of nonspecific secondary chronic duodenitis in patients with duodenal ulcer, which usually persists even after scarring of the ulcer.

Macrolides have a high ability to penetrate cells and accumulate in the mucous membrane of the stomach and duodenum, which increases their effectiveness against Helicobacter pylori

. In addition, macrolides have fewer contraindications and side effects and a higher eradication rate than tetracyclines, which can also accumulate in cells.

The most common side effects are caused by antibiotics such as tetracycline and furazolidone. Macrolides are well tolerated, and the need to discontinue therapy is noted no more than in 3% of cases (Maev I.V., Samsonov A.A.).

Of all macrolides, the greatest activity against Helicobacter pylori

has clarithromycin. This makes it the main drug from this group recommended for the treatment of Helicobacter pylori infection. Comparative results of the effectiveness of azithromycin and clarithromycin on the eradication rate indicate the greatest effectiveness of the latter by almost 30% (Maev I.V. et al.).

At the same time, the widespread use of macrolides (as well as other antibiotics) when implementing the “screen and treat” strategy can lead to the emergence of resistant pathogens other than Helicobacter pylori

.
Use of a macrolide at a single dose and duration of the shortest regimen for eradication of Helicobacter pylori
(clarithromycin 500 mg twice daily for 7 days) increased the resistance of macrolide-resistant pharyngeal
Streptococcus pneumoniae
in a placebo-controlled study in healthy volunteers.
This difference was statistically significant throughout the study over 180 days. The use of macrolides has been associated with increased resistance of Streptococcus pyogenes
and
Staphylococcus aureus
, which are common causes of community-acquired infections (Starostin B.D.).

There is information that macrolides lead to the development of cholestatic phenomena in the liver, which may be reflected in an increase in the concentration of secondary toxic bile salts in bile, impaired motility of the gastroduodenal zone and alkalization of the pyloric region. The consequence of this may be either an increase in the frequency of biliary reflux or compensatory hypergastrinemia with acidification of the antrum. Considering that the “mixed” version of reflux has a more pronounced damaging effect on the esophageal mucosa, it can be assumed that there is a relationship and the formation of a cascade of disorders in the acid-producing and acid-neutralizing functions of the upper gastrointestinal tract (Karimov M.M., Akhmatkhodzhaev A.A.).

Publications for healthcare professionals addressing the use of macrolides in the eradication of Helicobacter pylori

• Maev I.V., Samsonov A.A., Andreev N.G., Kochetov S.A. Clarithromycin as the main element of eradication therapy for diseases associated with Helicobacter pylori infection // Gastroenterology. 2011. No. 1.
• Maev I.V., Samsonov A.A. Duodenal ulcer: various approaches to modern conservative therapy // CONSILIUM MEDICUM. – 2004. – T. 1. – p. 6–11.
• Kornienko E.A., Parolova N.I. Antibiotic resistance of Helicobacter pylori in children and choice of therapy // Issues of modern pediatrics. – 2006. – Volume 5. – No. 5. – p. 46–50.
• Parolova N.I. Comparative assessment of the effectiveness of eradication therapy for H. pylori infection in children. Abstract of dissertation. PhD, 14.00.09 – pediatrics. SPbGPMA, St. Petersburg, 2008.
• Tsvetkova L.N., Goryacheva O.A., Gureev A.N., Nechaeva L.V. Rational pharmacotherapeutic approach to the treatment of duodenal ulcer in children // Materials of the XVIII Congress of Pediatric Gastroenterologists. – M. – 2011. – P. 303–310.

On the GastroScan.ru website in the “Literature” section there is a subsection “Antibiotics used in the treatment of gastrointestinal diseases,” containing articles on the use of antimicrobial agents in the treatment of diseases of the digestive tract.

Macrolides as prokinetics

Erythromycin and other macrolides interact with motilin receptors, imitating the action of the physiological regulator of the gastroduodenal migratory motor complex.
Erythromycin is capable of causing powerful peristaltic contractions, similar to those of the migratory motor complex, accelerating gastric emptying of liquid and solid food, however, erythromycin has not found widespread use in the treatment of patients with gastroesophageal reflux disease (GERD), since its effect on esophageal motility is practically absent. In addition, a significant decrease in the effectiveness of erythromycin was found against the background of gastric atony with long-term use, which creates obstacles to the use of this drug for GERD (Maev I.V. et al.). Erythromycin activates motilin receptors of smooth muscle cells of the gastrointestinal tract and cholinergic neurons of the intermuscular nerve plexus. In patients with GERD, erythromycin increases the basal pressure of the lower esophageal sphincter (LES). Its effect on transient relaxation of the LES (TRNS) has not been proven. Erythromycin does not affect the amplitude of primary peristaltic contractions of the esophagus, but reduces the number of episodes of “incomplete” contractions. It improves esophageal and gastric emptying in patients with gastroparesis, but this effect is absent in patients with GERD. In high doses, erythromycin is poorly tolerated; it has not found widespread use in gastroenterological practice (Ivashkin V.T., Trukhmanov A.S.).

Azithromycin at a dose of 250 mg per day in patients with GERD can shift the postprandial acid pocket distally, which reduces acid reflux without affecting the total number of refluxes. However, azithromycin has not found widespread use as a prokinetic agent due to side effects (Avdeev V.G.).

A number of macrolide drugs (alemcinal, mitemcinal), due to the fact that they are agonists of motilin receptors and are not antibiotics, are considered promising drugs for the treatment of functional dyspepsia and as such are mentioned in the Recommendations of the Russian Gastroenterological Association for the diagnosis and treatment of functional dyspepsia and 2011 ( Ivashkin V.T., Sheptulin A.A., etc.), and 2021. (Ivashkin V.T., Maev I.V., etc.). They are also offered for the treatment of other gastrointestinal diseases (GERD, reflux esophagitis, IBS-d, diabetic gastroparesis and others). However, none of the macrolides, based on the results of clinical trials of the second stage, could receive a positive conclusion, and today there is skepticism regarding the clinical use of both macrolide antibiotics and non-antibiotic macrolides as prokinetics: “as for such prokinetics as erythromycin, azithromycin, alemcinal , then their use for functional dyspepsia is not indicated due to the “non-physiological acceleration of gastric emptying”” (Sheptulin A.A., Kurbatova A.A.).

Publications for healthcare professionals addressing the use of macrolides as prokinetic agents

• Alekseeva E.V., Popova T.S., Baranov G.A. and others. Prokinetics in the treatment of intestinal failure syndrome // Kremlin Medicine. Clinical Bulletin. 2011. No. 4. pp. 125–129.
• Alekseeva E.V. Prokinetics in the treatment of intestinal failure syndrome in critically ill surgical patients. Abstract of dissertation. PhD, 01/14/20 - anesthesiology and resuscitation, 03/14/03 - pat. physiology. UC UDPRF, Moscow, 2010.
• Rosen R, Vandenplas Y, Singendonk M, et al. Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of NASPGHAN and ESPGHAN. // J Pediatr Gastroenterol Nutr. 2021 Mar;66(3):516-554.
• Rakitin B.V. Main recommendations in the article: Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of NASPGHAN and ESPGHAN. J Pediatr Gastroenterol Nutr. 2021.

On the website GastroScan.ru in the “Literature” section there is a subsection “Prokinetics”, containing publications for medical workers and medical students on the use of prokinetics in the treatment of diseases of the gastrointestinal tract.

Appendix 1. Macrolides in ATC

In the Anatomical Therapeutic Chemical Classification (ATC), in section “J Antimicrobial drugs for systemic use”, subsection “J01 Antibacterial drugs for systemic use” there is a group “J01FA Macrolides”, which includes the following codes: J01FA01 Erythromycin J01FA02 Spiramycin J01FA03
Midecamycin J01FA05 Oleandomycin J01FA06 Roxithromycin J01FA07 Josamycin J01FA08 Troleandomycin J01FA09 Clarithromycin J01FA10 Azithromycin J01FA11 Myocamycin J01FA12 Rokitamycin J01FA13 Dirithromycin J01FA14 Flurithromycin J01FA15 Telithromycin J01 FA16 Solithromycin

In the ATC section “A Drugs affecting the digestive tract and metabolism” there is a group “A02BD Combinations of drugs for the eradication of Helicobacter pylori

", which separately identifies combinations of drugs for the treatment of
Helicobacter pylori
diseases, including the macrolide clarithromycin:

A02BD04 Pantoprazole in combination with amoxicillin and clarithromycin A02BD05 Omeprazole, amoxicillin and clarithromycin A02BD06 Esomeprazole, amoxicillin and clarithromycin A02BD07 Lansoprazole, amoxicillin and clarithromycin A02BD09 Lansoprazole, clarithromycin and tinidazole A02 BD11 Pantoprazole, amoxicillin, clarithromycin and metronidazole

Tacrolimus has two ATC codes:

In section “L Antineoplastic drugs and immunomodulators”, group “L04A Immunosuppressants”, “L04AC Interleukin inhibitors”:

L04AD02 Tacrolimus

and in section “D Drugs for the treatment of skin diseases”:

D11AH01 Tacrolimus

Appendix 2. Trade names of drugs with active ingredients - macrolides

The State Register of Medicines of Russia contains (including those with expired registration) macrolide medicines with the following trade names*:

• international nonproprietary name (INN) clarithromycin
  (semi-synthetic antibiotic, 14-members): Arvicin, Bacticap, Biotericin, Zimbaktar, Kispar, Klabaks, Klabaks OD, Klarbakt, Clarithromycin-Akrikhin, Clarithromycin-Verte, Clarithromycin-J, Clarithromycin Zentiva, Clarithromycin Protech, Clarithromycin Pfizer, Clarithromycin Retard-OBL, Clarithromycin Sanofi, Clarithromycin SR, Clarithromycin-Teva, Clarithromycin Ecositrin, Clarithromycin-OBL, Clarithrosin, Claricin, Claricit, Claromin, Klasine, Klacid, Klacid SR, Clerimed, Coater, Lekoklar, Mycetinum, Romiclar, Seydon-Sanovel, SR-Klaren, Fromilid, Fromilid Uno, Ecositrin
• INN erythromycin
  (natural antibiotic, 14-members): Erythromycin, Erythromycin-AKOS, Erythromycin-LekT, Erythromycin-Ferein; complex active ingredient:
• erythromycin + zinc acetate
  : Zinerit
• erythromycin + isotretinoin
  : Isotrexin

* as of the beginning of October 2021 ** as of the beginning of February 2021
Macrolide medications have contraindications, side effects and application features; consultation with a specialist is required.

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