Antibiotics macrolides: names, application, indications for use. Macrolides in modern therapy of bacterial infections

For citation:Klyuchnikov S.O., Boldyrev V.B. The use of macrolides in children in modern conditions // RMZh. 2007. No. 21. S. 1552

In modern chemotherapy of bacterial infections in children, antibiotics, their semisynthetic and synthetic analogues, occupy the leading place. Today, more than 6,000 antibiotics have been described, of which about 50 have found application in medicine. The most widely used are b-lactams (penicillins and cephalosporins), macrolides (erythromycin, azithromycin, etc.), aminoglycosides (streptomycin, kanamycin, gentamicin, and others), tetracyclines, polypeptides (bacitracin, polymyxins, etc.), polyenes (nystatin, amphotericin B, etc.), steroids (fuzidin), etc.

By means of chemical and microbiological transformation, the so-called semi-synthetic antibiotics have been created, which have new properties that are valuable for medicine: acid- and enzyme resistance, an extended spectrum of antimicrobial action, better distribution in tissues and body fluids, and fewer side effects.
According to the type of antimicrobial action, antibiotics are divided into bacteriostatic and bactericidal, which is of practical importance when choosing the most effective therapy.
Comparative analysis of antibiotics is based on indicators of their effectiveness and harmlessness, determined by the severity of the antimicrobial action 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 tissues and fluids of the patient and the duration of their maintenance, the preservation of action in various environmental conditions. Important properties are also storage stability, ease of use with different methods of administration, a high chemotherapeutic index, the absence or weakness of toxic side effects, as well as the patient's allergization.
A discussion of the role of antibiotics in the treatment of childhood bacterial infections cannot be complete without addressing the issue of antimicrobial resistance. Due to the repeated and often unnecessary prescription of antibiotics, the incidence of infections caused by microorganisms that have become insensitive to the antibiotics used is increasing worldwide. An increase in the number of patients with immunodeficiency, the introduction of new invasive medical techniques, mutations of microorganisms themselves, and some others also play a role in the formation of resistance.
Antibiotic resistance is currently driving an increase in morbidity, mortality and health care costs worldwide. Because of the rapid increase in resistance, problems are especially acute in the treatment of bacterial infections in childhood. Of particular importance is resistance to penicillin and cephalosporin Strepto-coccus pneumoniae, multi-resistance of Haemophilus influenzae (insensitive to ampicillin, chloramphenicol, tetracycline and trimethoprim), the rapid spread of penicillin-resistant Neisseria meningitidis. Strains of Staphylococcus aureus resistant to methicycline are increasingly being found; all over the world doctors are faced with multiresistance of Enterobacteriaceae (for example, the number of isolated cultures of Klebsiella and Enterobacter species, which 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, group A streptococci to erythromycin.
While the emergence of antibiotic resistance may be an inevitable result of their widespread use, in practice it is undoubtedly possible to reduce the problem of resistance. For example, in the Netherlands, the use of systemic antibiotics is limited by the government program and the problem of resistance is not so acute.
In recent years, many new antibiotics of various pharmacological groups have been introduced into medical practice. However, the macrolide group is currently attracting the greatest attention of clinicians. This is facilitated by an increase in the frequency of drug allergy to penicillins and cephalosporins in the pediatric population, as well as the ineffectiveness of b-lactams in infections caused by intracellular pathogens.
Macrolides are now one of the most intensively developing classes of antibiotics due to their high efficiency and relative safety. They have a wide spectrum of antimicrobial activity and favorable pharmacokinetic properties, combining high efficiency in the treatment of infections and good patient tolerance.
The first macrolide antibiotic synthesized in 1952 was erythromycin, obtained by Vak-s-man 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, there has been a real scientific breakthrough: several, in a certain sense, unique in their qualities drugs have been created that keep the "high bar" to this day: azithromycin (Zitrocin, etc.), roxithromycin, clarithromycin, spiramycin, etc.
Macrolides got their name due to the presence of a macrocyclic lactone nucleus. 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 due to a violation of protein synthesis in a microbial cell by reversible binding to the 50S-subunit of the ribosome. 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. With the accumulation of high concentrations of the antibiotic in the focus of infection, macrolides have a so-called post-antibiotic effect, which means the suppression of the vital activity of bacteria when the action 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 more easily penetrate 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 excretion is through the gastrointestinal tract (about 2/3 of the drug), the rest of the amount is excreted through the kidneys and lungs, therefore, the dose adjustment of macrolides is required only in severe hepatic insufficiency.
The 14-membered 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 the activation of the hypothalamic-pituitary-supra-chechnic system. In addition, the stimulating effect of macrolides on neutrophilic phagocytosis and killing has been established.
Food has a multidirectional effect on the bioavailability of macrolides: does not affect the absorption of telithromycin, clarithromycin, josamycin and midecamycin acetate; slightly reduces the bioavailability of midecamycin, azithromycin and significantly - erythromycin and spiramycin. Simultaneous intake 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 medium, with a decrease in which ionization in the focus of inflammation increases and part of the drug turns into inactive forms. The optimal effect of erythromycin, clarithromycin, and especially azithromycin appears at pH\u003e 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 is hundreds of times higher than their serum concentration. An important feature of macrolides is their ability to accumulate in phagocytes with subsequent release in the focus of infection under the influence of bacterial stimuli and the reverse active capture of the drug "unused" by microorganisms. The maximum accumulation of macrolides is observed in the lung tissue, fluid lining the mucous membrane of the bronchi and alveoli, bronchial secretions, saliva, tonsils, middle ear, sinuses, gastrointestinal tract mucosa, prostate gland, conjunctiva and eye tissues, skin, bile, urethra, uterus, appendages and placenta. Meta-bolism of macroleads 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 highest affinity; b) clarithromycin, midecamycin, josamycin and roxithromycin are characterized by weak affinity; c) when using azithromycin, dirithromycin and spiramycin, there is no competitive binding with enzymes.
The half-life (T1 / 2) differs in different macrolides and may depend on the dose: the highest T1 / 2 has azithromycin - up to 96 hours, the smallest - erythromycin and josamycin - 1.5 hours (Table 1). Macrolides are excreted from the body mainly in the bile, undergoing enterohepatic recirculation.
In addition to the direct antimicrobial action on the cell, some macrolides have properties that enhance their effectiveness in the conditions of a macroorganism. Among them:
.? postantibiotic effect, manifested in the absence of the effect of resuming the growth of bacteria, despite the removal of the antibiotic from the body.
.? subinhibitory effect, however, it is difficult to use in therapy regimens, since the use of antibiotics in subinhibitory concentrations can cause an increase in resistance to it. It is used as a test to assess the distribution of the bacterial population by the degree of antibiotic sensitivity and the proportion of resistant individuals in it, a high number of which may indicate signs of resistance formation.
Macrolides are an indisputable alternative in case of allergy to b-lactams in the treatment of tonsillitis, sinusitis, otitis media, bronchitis, pneumonia, skin and soft tissue infections (Table 1). Considering that macrolides act equally well on both extracellular and intracellular pathogens, they have become first-line antibiotics in the treatment of many urogenital infections and the so-called atypical bronchopulmonary infections caused by chlamydia, mycoplasma, etc. Macrolides are also used in gastroenterology, and are increasingly included in the treatment of chronic gastroduodenitis associated with H. pylori (for example, clarithromycin). Macrolides are first-line antibiotics in the treatment of pertussis in children (moderate and severe), are included in the complex of therapeutic measures for pharyngeal diphtheria.
Macrolide resistance is not yet a serious problem in most regions of Russia, as evidenced by the results of the PeGAS-I multicenter study. According to the data presented, the prevalence of resistant clinical strains of S. pneumoniae is within 4%.
Modern macrolides have convenient forms of release: 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 it possible to use them in emergency situations.
All new macrolides in their pharmacological properties are significantly ahead of both erythromycin and midecamycin, having a more prolonged action, 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 the meal. The highest bioavailability is considered in roxithromycin (72-85%) and clarithromycin (52-55%) compared to azithromycin (37%), spiramycin (35%), etc.
From the 50s of the last century to the present, macrolides have been used with high efficiency, especially in the pathology of the upper respiratory tract. In terms of the frequency of use, macrolides occupy the 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, this is due to a number of reasons:
1. A high degree of accumulation of macrolides in the lymphoid tissue.
2. Efficiency (up to 90%) in patients with tonsillopharyngitis.
3. An increase in the frequency of excretion from the tonsils (especially with recurrent tonsillopharyngitis) of microorganisms producing b-lactamases capable of destroying penicillins, cephalosporins of the 1st generation (M. catarrhalis, St. aureus) and the high activity of macrolides in relation to these pathogens.
4. 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. Absence of influence on intestinal and pharyngeal microflora, moderate antifungal effect.
7. High safety range, allowing to double the dose of macrolide (azithromycin) 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. The activity of some macrolides against H. influenzae (azithromycin).
10. Lack of competing interactions in azalides with antifungal, antihistamines, which allows combined therapy in children with allergic manifestations, mycoses.
11. High activity of macrolides not only against nonspecific causative agents of diseases of the pharynx (GABHS, St. aureus, Str. Pneumonia), but also specific - N. meningitides, N. gonorrhoeas, Treponema pallidum, Legionella pneumonia, Lisferia monocytogenes, Corynebacterium diphtheriae, activity against anaerobes - the causative agents of paratonsillitis.
12. Immunomodulatory effect.
Despite the large number of positive criteria, in the past 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 the clinical ineffectiveness of macrolide antibiotics. Moreover, the high safety of macrolide antibiotics, and first of all 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. So, R. Cohen [cit. by 4], analyzing the clinical and bacteriological efficacy of the treatment of chronic tonsillitis with azithromycin at a course dose of 30 and 60 mg / kg, taken for 3 days, notes that bacteriological efficacy at a dose of 30 mg / kg is registered only in 58% of cases, whereas 60 mg / kg - reached 100% bacteriological eradication of the pathogen, comparable to a 10-day course of penicillin (95%).
The cost of macrolides on the modern pharmaceutical market varies in a wide range: from expensive original, undoubtedly, better quality drugs to more affordable generics, some of which are also of good quality (zitrocin, clerimed, roxiehexal, etc.), which ensures availability drugs of this group to all segments of the population.
But the doctor should be guided not only by the price of the drug when prescribing treatment for the child. Analysis of the clinical efficacy of various representatives of macrolides shows that the unreasonable and frequent prescription of a popular drug in one region during the year can negate the antimicrobial effect, since under these conditions protoplasts and L-forms are rapidly 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 efficacy of which have not been investigated 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 requiring attention if they persist for a long time and / or are poorly tolerated: allergic reactions (urticaria, itching of the skin); pain at the injection site; reactions from the gastrointestinal tract (nausea, vomiting, change in taste, pain and discomfort in the abdomen, diarrhea); dizziness and headache (extremely rare).
The most common adverse reactions are from the gastrointestinal tract. In the case of the use of azithromycin and clarithromycin, their frequency rarely reaches 12%, but when using erythromycin, the base can increase up to 32%. When using josamycin, clarithromycin, spiramycin and high doses of erythromycin (? 4 mg / day), acute cholestatic hepatitis may develop. When high doses of erythromycin are prescribed in a period from 36 hours to 8 days, reversible hearing loss is possible. High doses of erythromycin, telithromycin and spiramycin can cause prolongation of the QT interval and the occurrence of ventricular tachycardia of the "torsades de pointes" type. Cross-allergic reactions to all macrolides are extremely rare. Although macrolides can contribute to a change in the intestinal biocenosis, however, this becomes of clinical significance in very rare cases with the development of Clostridium dificille-associated pseudomembranous colitis, diarrhea, vaginal or oral candidiasis.
Among macrolide drugs, a special place is occupied by azithromycin, obtained and introduced into clinical practice in the early 90s of the XX century. This is the first representative of a new subgroup of antibiotics - azalides, the structure of the lactone ring of which contains a nitrogen atom. This restructuring of the erythromycin molecule gave the resulting compound new properties, including the expansion of the spectrum of antimicrobial action, the creation of high levels in tissues and cells, significantly exceeding the concentration in the blood (tissue-directed pharmacokinetics), and other properties that significantly distinguish it from antibiotics of the macrolide group.
Along with the retention of activity against gram-positive cocci, azithromycin (Zitrocin and others) exceeds erythromycin against Haemophilus influenzae, Moraxella catarrhalis, Neisseria spp., Campylobacler jejuni, Helicobacter pylori, Borrelia burgdorferi in activity. It is also active against some enterobacteriaceae: the value of its MIC90 in relation to Salmonella, Shigella, E. coli ranges from 4-16 mg / l. Azithromycin (Zitrocin and others) is active against some "atypical" microorganisms, as well as intracellular pathogens - Chlamydia spp., Mycoplasma spp. and etc.
Azithromycin is more stable at different pH values \u200b\u200bthan erythromycin. After taking a single dose, more than 37% of azithromycin is absorbed in the stomach compared to 25% of erythromycin. Food or the simultaneous use of antacids reduces the bioavailability of azithromycin, and therefore should be taken at least 1 hour before or 2 hours after a meal.
The concentration of azithromycin in tissues and cells exceeds that found in blood by 10-100 times; intracellularly concentrated in lysosomes. The average T1 / 2 value of azithromycin is 2-4 days. With the recommended treatment regimens (3 and 5 days), the drug in effective concentrations is maintained for 7 or more days. When deciding on repeated courses of antibiotic therapy, it is necessary to take into account the properties of azithromycin to accumulate in the tissues of the body, which makes it possible to shorten the duration of the course of treatment with azithromycin and provides a postantibiotic effect.
Azithromycin is rapidly incorporated into white blood cells (polynuclear cells, monocytes, lymphocytes), in high concentrations, and is found for a long time in alveolar macrophages and fibroblasts. When migrating to the focus of infection, polynuclear cells play a transport role, providing a high and long-lasting level of antibiotic in tissues and cells. Even when administered in maximum doses, azithromycin creates low concentrations in the blood, but has a high penetration into polynuclear cells (phagocytes), which are responsible for the clearance of pathogens from the focus of infection and the bloodstream.
The drug is not metabolized in the patient's body, does not suppress isoenzymes of the cytochrome P450 system. It is excreted from the patient's body mainly with feces and partially (~ 20%) with urine.
Thus, modern synthetic macrolides (azithromycin, clarithromycin, roxithromycin) are characterized by a wide spectrum of action: they are active against most gram-positive microorganisms, many gram-negative bacteria, “atypical” intracellular pathogens of respiratory infections; their spectrum of action also includes atypical mycobacteria, causative agents of a number of dangerous infectious diseases (rickettsia, brucella, borrelia, etc.) and some protozoa. They surpass natural macrolides not only in the breadth of the spectrum and the degree of antibacterial activity, but also in their bactericidal effect on many pathogens.
New macrolides (especially azithromycin) have improved pharmacokinetic properties: prolonged 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 completion of 3-5 -day courses of oral administration in a standard dose.
The interest of pediatricians in azithromycin is due to its high degree of accumulation in lymphoid tissue and long-term concentrations of the drug, providing a bactericidal effect, as well as rare side effects, lack of effect on the normal microflora of the oral cavity and intestines, and a low probability of drug interaction.
Tissue and cellular kinetics, prolonged action of new macrolides, the possibility of their effective use in short courses without the risk of developing serious adverse reactions cause a low incidence of antibiotic resistance.

All representatives of the list of macrolide drugs are antibacterial drugs. Their chemical structure is based on a macrocyclic lactone ring. Hence the name of the group. They are used to combat various types of bacteria. And due to the fact that these funds are quite effective, medicine uses them very actively.

In what cases are drugs of the macrolide group prescribed?

The great advantage of macrolides is that they are active against harmful gram-positive cocci. Antibiotics of this group can easily cope with pneumococci, pyogenic streptococci, atypical mycobacteria. Among other things, they destroy:

• legionella;
• spirochetes;
• chlamydia;
• anaerobes (practically all, except for B. fragilis);
• listeria;
• mycoplasma;
• ureaplasma;
• campylobacter and some other harmful microorganisms.

Based on this list, the main indications for the use of macrolide preparations were also compiled. Prescribe medicines for:

• streptococcal tonsilopharyngitis;
• whooping cough;
• exacerbations of chronic bronchitis;
• community-acquired pneumonia (including atypical);
• diphtheria;
• periostitis;
• syphilis;
• chlamydia;
• mycobacteriosis;
• toxoplasmosis;
• extra-lateral lymphogranulomas;
• severe acne;
• periodontitis.

In some cases, macrolides are used not only for treatment, but also for prevention. For example, a course of these antibacterial drugs will help prevent whooping cough in those who have had contact with infected people. Antibiotics of this group are also prescribed for the rehabilitation of patients who are carriers of meningococcus. And they can also be a good prevention of rheumatism or endocarditis.

The names of antibiotic drugs of the macrolide group

Depending on how many carbon atoms are on the lactone ring, the drugs are divided into groups of 14-, 15- or 16-membered. In addition to the fact that these antibacterial medicines destroy pathogens, they also help to strengthen the immune system and can eliminate not too actively progressive inflammatory processes.

The main macrolide antibiotics include the following drugs:

1. Erythromycin it is recommended to take before meals. Otherwise, its bioavailability will be markedly reduced. Despite the fact that this is a strong antibacterial drug, in case of an urgent need to drink it is allowed even during pregnancy and lactation.
2. Spiramycin active even against bacteria that adapt to 14- and 15-membered macrolides. Its concentration in tissues is very high.
3. A macrolide drug named Clarithromycin, fights against Helicobacter and atypical mycobacteria.
4. Therapy Roxithromycin quite well tolerated by patients.
5. Azithromycin so strong that it should be taken once a day.
6. Popularity Josamycin due to its activity against most resistant species of streptococci and staphylococci.

Almost all macrolides from this list of drugs can be prescribed for bronchitis. In addition, they can be used to fight bacteria.

Surely every person at least once in his life has come across an infectious disease, the treatment of which cannot do without taking antibiotics, and many have at least a general idea of \u200b\u200bthe properties of these drugs and the peculiarities of their use. Antibiotics are divided into groups, the differences between which are mainly in the chemical composition, mechanism of action and spectrum of activity.

In addition, drugs of different generations are classified in each group of antibiotics: antibiotics of the first, second generation, etc. The last, new generation of antibiotics differs from the previous ones in fewer side effects, greater efficiency, and ease of administration. In this article, we will consider which drugs of the latest generation are included in the list of antibiotics from the macrolide group, and what are their features.

Characteristics and application of macrolides

Antibiotics belonging to the pharmacological group of macrolides are considered one of the least toxic to the human body. These are complex compounds of natural and semi-synthetic origin. They are well tolerated by most patients, do not cause adverse reactions characteristic of other antibiotic groups. A distinctive feature of macrolides is the ability to penetrate into cells, creating high concentrations in them, quickly and well distributed in inflamed tissues and organs.

Macrolides have the following effect:

• bacteriostatic;
• anti-inflammatory;
• immunomodulatory.

The main indications for taking macrolide antibiotics are:

• infections of the respiratory tract and oral cavity (, otitis media, sinusitis, tonsillitis, bronchitis, pneumonia, diphtheria, tuberculosis, etc.);
• diseases of the biliary tract;
• infectious eye diseases (conjunctivitis, trachoma, etc.);
• peptic ulcer;
• infections of the skin and soft tissues (severe acne, erysipelas, mastitis, etc.);
• urogenital infections, etc.

Modern macrolides

The first drug in the macrolide group was erythromycin. It should be noted that this drug is used in medical practice to this day, and its use shows good results. However, subsequently invented macrolide preparations, due to the fact that they have improved pharmacokinetic and microbiological parameters, are more preferable.

A new generation of antibiotic macrolide is a substance from the group of azalides - azithromycin (trade names: Summamed, Azithromax, Zatrin, Zomax, etc.). This drug is an erythromycin derivative that additionally contains a nitrogen atom. The advantages of this drug are:

• high absorption rate;
• long half-life;
• acidic stability
• the ability to be transported by leukocytes to the focus of inflammation;
• the possibility of reducing the duration of therapy and the frequency of drug intake (once a day for 3 - 5 days).

Azithromycin is active against:

• staphylococci;
• streptococci;
• chlamydia;
• whooping cough;
• gardnerellam;
• mycoplasma;
• mycobacteria;
• causative agents of syphilis and some other bacteria.

To a greater extent, the accumulation of the drug is observed in the lungs, bronchial secretions, nasal sinuses, tonsils, kidneys.

Latest generation macrolides for bronchitis

Azithromycin-based preparations are characterized by the most optimal spectrum of antimicrobial activity in relation to typical and atypical pathogens of bronchitis. They easily penetrate bronchial secretions and phlegm, block protein synthesis in bacterial cells, thereby preventing bacteria from multiplying. Macrolides can be used both for acute bacterial bronchitis and for exacerbation of chronic bronchitis.

Macrolides are a class of antibiotics whose chemical structure is based on a macrocyclic lactone ring. Depending on the number of carbon atoms in the ring, macrolides are subdivided into 14-membered (erythromycin, roxithromycin, clarithromycin), 15-membered (azithromycin) and 16-membered (midecamycin, spiramycin, josamycin). The main clinical significance is the activity of macrolides against gram-positive cocci and intracellular pathogens (mycoplasma, chlamydia, campylobacter, legionella). Macrolides are among the least toxic antibiotics.

Classification of macrolides

Mechanism of action

The antimicrobial effect is due to a violation of protein synthesis on the ribosomes of the microbial cell. As a rule, macrolides have a bacteriostatic effect, but in high concentrations they are capable of acting bactericidal on GABHS, pneumococcus, pertussis and diphtheria pathogens. Macrolides show PAE against gram-positive cocci. In addition to antibacterial action, macrolides have immunomodulatory and moderate anti-inflammatory activity.

Spectrum of activity

Macrolides are active against gram-positive cocci such as S.pyogenes, S.pneumoniae, S.aureus (except for MRSA). In recent years, an increase in resistance has been noted, but at the same time 16-membered macrolides in some cases may remain active against pneumococci and pyogenic streptococci resistant to 14- and 15-membered drugs.

Macrolides act on the causative agents of whooping cough and diphtheria, moraxella, legionella, campylobacter, listeria, spirochetes, chlamydia, mycoplasma, ureaplasma, anaerobes (excluding B.fragilis).

Azithromycin is superior to other macrolides in activity against H.influenzae, and clarithromycin against H. pylori and atypical mycobacteria ( M.avium and etc.). The effect of clarithromycin on H.influenzae and a number of other pathogens enhances its active metabolite - 14-hydroxyclarithromycin. Spiramycin, azithromycin and roxithromycin are active against some protozoa ( T.gondii, Cryptosporidium spp.).

Microorganisms of the family Enterobacteriaceae, Pseudomonas spp. and Acinetobacter spp. have natural resistance to all macrolides.

Pharmacokinetics

The absorption of macrolides in the gastrointestinal tract depends on the type of drug, dosage form and the presence of food. Food significantly reduces the bioavailability of erythromycin, to a lesser extent - roxithromycin, azithromycin and midecamycin, practically does not affect the bioavailability of clarithromycin, spiramycin and josamycin.

Macrolides belong to tissue antibiotics, since their serum concentrations are much lower than tissue antibiotics and vary between drugs. The highest serum concentrations are found in roxithromycin, the lowest in azithromycin.

Macrolides bind to blood plasma proteins to varying degrees. The highest binding to plasma proteins is observed in roxithromycin (more than 90%), the lowest in spiramycin (less than 20%). They are well distributed in the body, creating high concentrations in various tissues and organs (including the prostate gland), especially during inflammation. In this case, macrolides penetrate into the cells and create high intracellular concentrations. Poorly pass through the BBB and the blood-ophthalmic barrier. Pass through the placenta and pass into breast milk.

Macrolides are metabolized in the liver with the participation of the cytochrome P-450 microsomal system, metabolites are excreted mainly in the bile. One of the metabolites of clarithromycin has antimicrobial activity. Metabolites are excreted mainly in the bile, renal excretion is 5-10%. The half-life of drugs ranges from 1 hour (midecamycin) to 55 hours (azithromycin). In renal failure, most macrolides (except for clarithromycin and roxithromycin) do not change this parameter. With liver cirrhosis, a significant increase in the half-life of erythromycin and josamycin is possible.

Adverse reactions

Macrolides are one of the safest AMP groups. HPs are generally rare.

Gastrointestinal tract: pain or discomfort in the abdomen, nausea, vomiting, diarrhea (most often they are caused by erythromycin, which has a prokinetic effect, less often - spiramycin and josamycin).

Liver: a transient increase in transaminase activity, cholestatic hepatitis, which can manifest itself as jaundice, fever, general malaise, weakness, abdominal pain, nausea, vomiting (more often when using erythromycin and clarithromycin, very rarely when using spiramycin and josamycin).

CNS: headache, dizziness, hearing impairment (rarely with intravenous administration of large doses of erythromycin or clarithromycin).

A heart: lengthening the QT interval on the electrocardiogram (rare).

Local reactions: phlebitis and thrombophlebitis with intravenous administration, caused by a local irritant effect (macrolides cannot be administered in concentrated form and jet, they are administered only by slow infusion).

Allergic reactions (rash, urticaria, etc.) are very rare.

Indications

STIs: chlamydia, syphilis (except neurosyphilis), chancre, lymphogranuloma venereum.

Oral infections: periodontitis, periostitis.

Severe acne (erythromycin, azithromycin).

Campylobacter gastroenteritis (erythromycin).

Eradication H. pylori with gastric ulcer and duodenal ulcer (clarithromycin in combination with amoxicillin, metronidazole and antisecretory drugs).

Toxoplasmosis (usually spiramycin).

Cryptosporidiosis (spiramycin, roxithromycin).

Prevention and treatment of mycobacteriosis caused by M.avium in AIDS patients (clarithromycin, azithromycin).

Preventive use:

prevention of whooping cough in people in contact with patients (erythromycin);

debridement of meningococcal carriers (spiramycin);

year-round prevention of rheumatism in case of allergy to penicillin (erythromycin);

prevention of endocarditis in dentistry (azithromycin, clarithromycin);

bowel decontamination before colon surgery (erythromycin in combination with kanamycin).

Contraindications

Allergic reaction to macrolides.

Pregnancy (clarithromycin, midecamycin, roxithromycin).

Breastfeeding (josamycin, clarithromycin, midecamycin, roxithromycin, spiramycin).

Warnings

Pregnancy. There is evidence of undesirable effects of clarithromycin on the fetus. There is no information to prove the safety of roxithromycin and midecamycin for the fetus, so they should also not be prescribed during pregnancy. Erythromycin, josamycin and spiramycin do not adversely affect the fetus and can be administered to pregnant women. Azithromycin is used during pregnancy in case of emergency.

Lactation. Most macrolides pass into breast milk (data on azithromycin are not available). Safety information for a breastfed baby is available only for erythromycin. The use of other macrolides in women who are breastfeeding should be avoided whenever possible.

Pediatrics. The safety of clarithromycin in children under 6 months of age has not been established. The half-life of roxithromycin in children may increase up to 20 hours.

Geriatrics. There are no restrictions for the use of macrolides in elderly people, however, one must take into account possible age-related changes in liver function, as well as an increased risk of hearing impairment when using erythromycin.

Impaired renal function. With a decrease in creatinine clearance less than 30 ml / min, the elimination half-life of clarithromycin can increase up to 20 hours, and its active metabolite - up to 40 hours. The half-life of roxithromycin can increase up to 15 hours with a decrease in creatinine clearance to 10 ml / min. In such situations, it may be necessary to adjust the dosage regimen of these macrolides.

Liver dysfunction. In severe liver disease, macrolides should be used with caution, since the half-life may increase and the risk of their hepatotoxicity may increase, especially for drugs such as erythromycin and josamycin.

Heart disease. Use with caution when prolonging the QT interval on the electrocardiogram.

Drug interactions

Most of the drug interactions of macrolides are based on their inhibition of cytochrome P-450 in the liver. According to the severity of its inhibition, macrolides can be distributed in the following order: clarithromycin\u003e erythromycin\u003e josamycin \u003d midecamycin\u003e roxithromycin\u003e azithromycin\u003e spiramycin. Macrolides inhibit metabolism and increase the blood concentration of indirect anticoagulants, theophylline, carbamazepine, valproic acid, disopyramide, ergot preparations, cyclosporine, which increases the risk of developing HP, characteristic of these drugs, and may require correction of their dosage regimen. It is not recommended to combine macrolides (except for spiramycin) with terfenadine, astemizole and cisapride due to the risk of developing severe cardiac arrhythmias caused by prolonged QT interval.

Macrolides can increase the bioavailability of digoxin when taken orally by weakening its inactivation by the intestinal microflora.

Antacids reduce the absorption of macrolides, especially azithromycin, in the gastrointestinal tract.

Rifampicin increases the metabolism of macrolides in the liver and lowers their concentration in the blood.

Macrolides should not be combined with lincosamides due to a similar mechanism of action and possible competition.

Erythromycin, especially when administered intravenously, is able to enhance the absorption of alcohol in the gastrointestinal tract and increase its concentration in the blood.

Information for patients

Most macrolides should be taken orally 1 hour before or 2 hours after a meal, and only clarithromycin, spiramycin, and josamycin can be taken with or without food.

Erythromycin should be taken by mouth with a full glass of water.

Prepare and take liquid dosage forms for oral administration in accordance with the attached instructions.

Strictly adhere to the regimen and treatment regimen during the entire course of therapy, do not skip the dose and take it at regular intervals. If a dose is missed, take it as soon as possible; do not take if it is almost time for the next dose; do not double the dose. Maintain the duration of therapy, especially with streptococcal infections.

Do not use drugs with an expired date.

Consult a doctor if there is no improvement within a few days or new symptoms appear.

Do not take macrolides with antacids.

Do not drink alcohol during treatment with erythromycin.

Table. Preparations of the macrolide group.
Main characteristics and application features

INN	Lecform LS	F (inside),%	T ½, h *	Dosage regimen	Features of drugs
Erythromycin	Tab. 0.1 g; 0.2 g; 0.25 g and 0.5 g Gran. d / suspension. 0.125 g / 5 ml; 0.2 g / 5 ml; 0.4 g / 5 ml Candles, 0.05 g and 0.1 g (for children) Susp. d / ingestion 0.125 g / 5 ml; 0.25 g / 5 ml Por. d / in. 0.05 g; 0.1 g; 0.2 g per bottle.	30-65	1,5-2,5	Inside (1 hour before meals) Adults: 0.25-0.5 g every 6 hours; with streptococcal tonsillopharyngitis - 0.25 g every 8-12 hours; for the prevention of rheumatism - 0.25 g every 12 hours Children: up to 1 month: see the section "Use of AMP in children"; over 1 month: 40-50 mg / kg / day in 3-4 divided doses (can be used rectally) I / O Adults: 0.5-1.0 g every 6 hours Children: 30 mg / kg / day in 2-4 introductions Before intravenous administration, a single dose is diluted in at least 250 ml of 0.9% sodium chloride solution, injected within 45-60 minutes	Food significantly reduces oral bioavailability. Frequent development of HP from the gastrointestinal tract. Clinically significant interaction with other drugs (theophylline, carbamazepine, terfenadine, cisapride, disopyramide, cyclosporine, etc.). Can be used during pregnancy and breastfeeding
Clarithromycin	Tab. 0.25 g and 0.5 g Tab. slowed down vysv. 0.5 g Por. d / suspension 0.125 g / 5 ml Por. d / in. 0.5 g per bottle.	50-55	3-7	Adults: 0.25-0.5 g every 12 hours; for the prevention of endocarditis - 0.5 g 1 hour before the procedure Children over 6 months: 15 mg / kg / day in 2 divided doses; for the prevention of endocarditis - 15 mg / kg 1 hour before the procedure I / O Adults: 0.5 g every 12 hours Before intravenous administration, a single dose is diluted in at least 250 ml of 0.9% sodium chloride solution, administered within 45-60 minutes	Differences from erythromycin: - higher activity in relation H. pylori and atypical mycobacteria; - better bioavailability when taken orally; - the presence of an active metabolite; - with renal failure, an increase in T ½ is possible; - not used in children under 6 months of age, during pregnancy and breastfeeding
Roxithromycin	Tab. 0.05 g; 0.1 g; 0.15 g; 0.3 g	50	10-12	Inside (1 hour before meals) Adults: 0.3 g / day in 1 or 2 doses Children: 5-8 mg / kg / day in 2 divided doses	Differences from erythromycin: - higher bioavailability; - higher concentrations in blood and tissues; - food does not affect absorption; - in severe renal failure, an increase in T ½ is possible; - better tolerated;
Azithromycin	Caps. 0.25 g Tab. 0.125 g; 0.5 g Por. d / suspension 0.2 g / 5 ml per bottle. 15 ml and 30 ml each; 0.1 g / 5 ml in a bottle. 20 ml each Syrup 100 mg / 5 ml; 200 mg / 5 ml	37	35-55	Inside (1 hour before meals) Adults: 0.5 g / day for 3 days or on the 1st day 0.5 g, 2-5 days - 0.25 g each, at one time; with acute chlamydial urethritis and cervicitis - 1.0 g once Children: 10 mg / kg / day for 3 days or on the 1st day - 10 mg / kg, 2-5 days - 5 mg / kg, in one dose; at CCA - 30 mg / kg once or 10 mg / kg / day for 3 days	Differences from erythromycin: - more active in relation to H.influenzae; - acts on some enterobacteria; - bioavailability is less dependent on food intake, but it is desirable to take on an empty stomach; - the highest concentrations among macrolides in tissues, but low in blood; - better tolerated; - taken once a day; - short courses are possible (3-5 days); - for acute urogenital chlamydia and CCA in children, it can be used once
Spiramycin	Tab. 1.5 million IU and 3 million IU Gran. d / suspension. 1.5 million IU; 375 thousand IU; 750 thousand IU per pack. Por. lyoph. d / in. 1.5 million IU	10-60	6-12	Inside (regardless of food intake) Adults: 6-9 million IU / day in 2-3 doses Children: body weight up to 10 kg - 2-4 pack. 375 thousand IU per day in 2 doses; 10-20 kg - 2-4 pack. 750 thousand IU per day in 2 doses; more than 20 kg - 1.5 million IU / 10 kg / day in 2 doses I / O Adults: 4.5-9 million IU / day in 3 doses Before intravenous administration, a single dose is dissolved in 4 ml of water for injection, and then 100 ml of 5% glucose solution is added; introduce within 1 hour	Differences from erythromycin: - active against some streptococci resistant to 14- and 15-membered macrolides; - creates higher concentrations in tissues; - better tolerated; - clinically significant drug interactions have not been established; - used for toxoplasmosis and cryptosporidiosis; - children are prescribed only inside;
Josamycin	Tab. 0.5 g Suspension. 0.15 g / 5 ml per bottle. 100 ml and 0.3 g / 5 ml in a bottle. 100 ml each	ND	1,5-2,5	Inside Adults: 0.5 g every 8 hours With chlamydia in pregnant women - 0.75 mg every 8 hours for 7 days Children: 30-50 mg / kg / day in 3 divided doses	Differences from erythromycin: - active against some erythromycin-resistant strains of streptococci and staphylococci; - food does not affect bioavailability; - better tolerated; - drug interactions are less likely; - not applicable for breastfeeding
Midecamycin	Tab. 0.4 g	ND	1,0-1,5	Inside (1 hour before meals) Adults and children over 12 years old: 0.4 g every 8 hours	Differences from erythromycin: - bioavailability is less dependent on food, but it is advisable to take 1 hour before meals; - higher concentrations in tissues; - better tolerated; - drug interactions are less likely; - does not apply during pregnancy and lactation
Midecamycin acetate	Por. d / suspension. for oral administration 0.175 g / 5 ml in a bottle. 115 ml each	ND	1,0-1,5	Inside (1 hour before meals) Children under 12: 30-50 mg / kg / day in 2-3 doses	Differences from midecamycin: - more active in vitro; - better absorbed in the digestive tract; - creates higher concentrations in blood and tissues

* With normal kidney function

A drug	Commercial names	Routes of administration and doses
ERYTHROMYCIN	GRUNAMICIN	Inactivated in an acidic environment, food significantly reduces bioavailability, inhibits cytochrome P-450 liver, erythromycin preparations (other than estolate) can be prescribed during pregnancy and breastfeeding
CLARITRO- MITSIN *	CLUBAX, CLACID, FROMILID	Has a pronounced effect on Helicobacter pylori and atypical mycobacteria, resistant in an acidic environment, undergoes presystemic elimination, forms an active metabolite, is excreted in the urine, contraindicated in children under 6 months of age, during pregnancy and breastfeeding
ROSKISTRO-MITSIN	RULID	Suppresses protozoa, is stable in an acidic environment, does not affect the activity of cytochrome P-450
AZITROMYCIN	SUMAMED	More than other macrolides inhibits hemophilic bacillus, is active against protozoa and some enterobacteria (shigella, salmonella, cholera vibrio), is stable in an acidic environment, undergoes presystemic elimination, creates the highest concentrations in cells, has a long half-elimination period
JOSAMYCINE	VILPRAFEN	Suppresses some erythromycin-resistant strains of streptococci and staphylococci, does not affect cytochrome activity P-450, contraindicated in pregnancy and breastfeeding

End of table 6

* Clathrithromycin Wed(klacid Wed) is available in matrix tablets with a sustained release of the antibiotic, prescribed 1 time per day.

Macrolides, depending on the type of microorganisms and dose, have a bacteriostatic or bactericidal effect. They suppress gram-positive bacteria that produce β-lactamase, as well as microorganisms localized intracellularly - listeria, campylobacter, atypical mycobacteria, legionella, spirochetes, mycoplasma, ureaplasma. Clarithromycin is superior to other macrolides in activity against Helicobacter pylori and atypical mycobacteria, azithromycin has a stronger effect on Haemophilus influenzae. Roxithromycin, azithromycin and spiromycin inhibit protozoa - Toxoplasma and Cryptosporidium.

Antimicrobial spectrum of macrolides: Staphylococcus aureus (sensitive to methicillin), hemolytic streptococci, pneumococci, green streptococcus, meningococci, gonococci, moraxella, corynebacterium diphtheria, listeria, clostridia of gas gangrene, causative agent of gas gangrene, hemophilus influenzae Helicobacter pylori, the causative agent of whooping cough, atypical microbacteria (except Mycobacterium fortuitum), bacteroids ( Bacteroides melaninogenicus, B. oralis), legionella, mycoplasma, ureaplasma, chlamydia, spirochete.

Natural resistance to macrolides is characteristic of enterococci, intestinal microflora, Pseudomonas aeruginosa, a number of anaerobic pathogens that cause severe purulent-inflammatory processes. Macrolides, without disturbing the colonization activity of intestinal bacteria, do not lead to the development of dysbiosis.

Secondary resistance of microorganisms to macrolides develops rapidly, so the course of treatment should be short (up to 7 days), otherwise they must be combined with other antibiotics. It should be emphasized that in the event of secondary resistance to one of the macrolides, it applies to all other antibiotics of this group and even to drugs from other groups: lincomycin and penicillins.

Pharmacokinetics.Some macrolides can be administered intravenously (erythromycin phosphate, spiramycin). The subcutaneous and intramuscular routes are not used, as injections are painful and local tissue damage is noted.

All macrolides can be administered orally. Oleandomycin and antibiotics of the II and III generations are more acid-resistant, so they can be taken regardless of food intake.

Regardless of the antimicrobial action, macrolides have the following effects:

They prevent hypersecretion of bronchial mucus, exerting a mucoregulatory effect (with a dry, unproductive cough, it is recommended to additionally take mucolytic agents);

Weaken the inflammatory reaction as a result of the antioxidant effect and inhibition of the synthesis of prostaglandins, leukotrienes and interleukins (used to treat panbronchitis and steroid-dependent bronchial asthma);

Show immunomodulatory properties.

A unique feature of clarithromycin is its antitumor effect.

Macrolides are absorbed into the bloodstream from the duodenum. The base of erythromycin is largely destroyed by gastric juice, therefore it is used in the form of esters, as well as enteric-coated tablets and capsules. New macrolides are resistant to an acidic environment, absorbed quickly and completely, although many drugs undergo first-pass elimination. Food reduces the bioavailability of macrolides by 40-50% (except for josamycin and spiramycin).

The connection of macrolides with blood proteins varies from 7 to 95%. They poorly penetrate the blood-brain and blood-ophthalmic barriers, accumulate in the secretion of the prostate gland (40% of the concentration in the blood), middle ear exudate (50%), tonsils, lungs, spleen, liver, kidneys, bones, overcome the placental barrier (5-20 %), enter breast milk (50%). The content of antibiotics is much higher inside cells than in blood. Macrolide-enriched neutrophils deliver these antibiotics to the foci of infection.

Macrolides are used for infections of the respiratory tract, skin and soft tissues, oral cavity, genitourinary system caused by intracellular pathogens and gram-positive bacteria resistant to penicillins and cephalosporins. The main indications for their appointment are as follows:

Upper respiratory tract infections - streptococcal tonsillopharyngitis, acute sinusitis;

Lower respiratory tract infections - exacerbation of chronic bronchitis, community-acquired pneumonia, including atypical (in 20 - 25% of patients, pneumonia is caused by mycoplasma or chlamydial infection);

Diphtheria (erythromycin in combination with anti-diphtheria serum);

Skin and soft tissue infections;

Oral infections - periodontitis, periostitis;

Campylobacter gastroenteritis (erythromycin);

Eradication Helicobacter pylori with peptic ulcer (clarithromycin, azithromycin);

Trachoma (azithromycin);

Sexually transmitted infections - chlamydia, lymphogranuloma venereum, syphilis without lesions of the nervous system, chancre;

Lyme disease (azithromycin);

Infections caused by atypical microbacteria in AIDS patients (clarithromycin, azithromycin);

Prevention of whooping cough in people in contact with patients (erythromycin);

Remediation of meningococcal carriers (spiramycin);

Year-round prevention of rheumatism in case of allergy to benzylpenicillin (erythromycin);

Prevention of endocarditis in dentistry (clarithromycin, azithromycin).

In the future, macrolides will find application in the therapy of atherosclerosis, since the etiological factor of this disease in 55% of cases is Chlamidia pneumonae.

Macrolides are rated as low-toxic antimicrobial agents. Occasionally they cause allergic reactions in the form of fever, coded rash, urticaria, eosinophilia.

Erythromycin and, to a lesser extent, josamycin and spiramycin cause dyspeptic disorders. After 10 to 20 days of treatment with erythromycin and clarithromycin, cholestatic hepatitis may develop with nausea, vomiting, spastic abdominal pain, fever, jaundice, and an increase in the activity of aminotransferases in the blood. Liver biopsy reveals cholestasis, parenchymal necrosis, periportal cell infiltration. With intravenous infusion of macrolides, thrombophlebitis, reversible hearing impairment, lengthening of the interval Q - T and other forms of arrhythmias.

Erythromycin and clarithromycin inhibiting cytochrome P-450 liver, prolong and enhance the effect of drugs with metabolic clearance (tranquilizers, carbamazepine, valproate, theophylline, disopyramide, ergometrine, corticosteroids, astemizole, terfenadine, cyclosporine). New macrolides only slightly alter the metabolism of xenobiotics.

Macrolides are contraindicated in hypersensitivity, pregnancy and breastfeeding. In patients with renal insufficiency, the dose of clarithromycin is reduced in accordance with creatinine clearance. In severe liver disease, dose adjustment of all macrolides is necessary. At the time of antibiotic therapy, you should stop drinking alcoholic beverages.

Aminoglycosides

Aminoglycoside antibiotics are amino sugars linked by a glycosidic bond to hexose (aminocyclitol ring). They are used only parenterally, poorly penetrate cells and cerebrospinal fluid, and are excreted unchanged by the kidneys. Aminoglycosides are considered the drugs of choice for infections caused by anaerobic gram-negative bacteria (tuberculosis, hospital infections, septic endocarditis). Their widespread use is hindered by pronounced oto-, vestibulo- and nephrotoxicity.

The history of the clinical use of aminoglycosides goes back about 60 years. In the early 1940s, the American microbiologist, future Nobel laureate Zelman Waxman, impressed by the discovery of benzylpenicillin, which suppresses pyogenic microflora, set out to create an antibiotic effective for tuberculosis. For this, he investigated the antimicrobial effect of a large number of soil fungi. In 1943, from the culture fluid Streptomyces griseus streptomycin was isolated, which has a detrimental effect on tuberculosis bacteria, many anaerobic gram-positive and gram-negative bacteria. Since 1946, streptomycin has been widely used in clinical practice.

In 1949 Z. Waxman and his collaborators obtained neomycin from culture Streptomyces fradie... In 1957, scientists at the Japan National Health Center isolated kanamycin from Streptomyces kanamyceticus.

Gentamicin (described in 1963) and netilmicin are produced by actinomycetes Microspora.

Tobramycin and amikacin have been known since the early 1970s. Tobramycin is part of the nebramycin aminoglycoside produced Streptomyces tenebrarius... Amikacin is a semi-synthetic acylated derivative of kanamycin. The search for new aminoglycoside antibiotics was suspended due to the appearance of less toxic β-lactams and fluoroquinolones with the same antimicrobial activity as aminoglycosides.

There are 3 generations of aminoglycoside antibiotics:

I generation - streptomycin, kanamycin, neomycin (used only for local action);

2nd generation - gentamicin, tobramycin, amikacin;

III generation - netilmicin (has less oto- and vestibulotoxicity).

Streptomycin and kanamycin suppress mycobacterium tuberculosis, streptomycin is active against brucella, the causative agents of plague and tularemia. The most sensitive to neomycin are Escherichia coli, Klebsiella, Enterococcus, Proteus and Enterobacter species. Antibiotics of the II-III generation are toxic for E. coli, Klebsiella, Serration, Pseudomonas aeruginosa, Proteus species, Enterobacter and Acinetobacter. All aminoglycosides inhibit 90% of Staphylococcus aureus strains. Resistance to aminoglycosides is characteristic of anaerobic bacteria, hemolytic streptococci, and pneumococci.

The bactericidal effect of aminoglycosides is due to the formation of abnormal proteins and the detergent effect on the lipoprotein cytoplasmic membrane of microorganisms.

Antibiotics of the β-lactam group, inhibiting the synthesis of the cell wall, potentiate the antimicrobial effect of aminoglycosides. On the contrary, chloramphenicol, blocking transport systems in the cytoplasmic membrane, weakens their effect.

The mechanisms of acquired resistance of microorganisms to aminoglycosides are as follows:

Enzymes are synthesized that inactivate antibiotics;

The permeability of the porin channels of the cell wall of gram-negative bacteria decreases;

The binding of aminoglycosides to ribosomes is impaired;

The release of aminoglycosides from the bacterial cell is accelerated.

Streptomycin and gentamicin lose their activity under the influence of various enzymes, therefore streptomycin-resistant strains of microorganisms can react to gentamicin. Kanamycin, gentamicin, tobramycin, amikacin and netilmicin are inactivated by polyfunctional enzymes, and as a result, cross-resistance forms between them.

1% of the dose of aminoglycosides is absorbed from the intestine, the rest is excreted unchanged in the feces. The absorption of gentamicin is increased in peptic ulcer disease and ulcerative colitis. Aminoglycosides can create toxic concentrations in the blood when taken for a long time against the background of renal failure, injected into the body cavity, applied to extensive burns and wounds. When injected into the muscles, they have high bioavailability, creating a maximum blood level in 60 - 90 minutes.

Aminoglycosides are distributed in the extracellular fluid, to a small extent (10%) bind to blood albumin, poorly penetrate into cells, cerebrospinal fluid, the environment of the eye, the mucous membrane of the respiratory tract, slowly enter the pleural and synovial fluids, accumulate in the cortical layer of the kidneys, endolymph and perilymph of the inner ear. With meningitis and in newborns, the level of aminoglycosides in the brain reaches 25% of the content in the blood (normally 10%). Their concentration in bile is 30% of the concentration in blood. This is due to the active secretion of antibiotics in the bile ducts of the liver.

The intake of aminoglycosides by women in late pregnancy is accompanied by an intensive intake of the drug into the fetal blood, which can cause sensorineural hearing loss in a child. Aminoglycosides pass into breast milk.

Aminoglycosides are excreted unchanged by filtration in the glomeruli of the kidneys, creating a high concentration in the urine (with hyperosmoticity of urine, antimicrobial activity is lost).

The pharmacokinetics of aminoglycosides changes in pathological conditions. In renal failure, the elimination half-life is 20 to 40 times longer. In contrast, with fibrosis of the bladder, elimination is accelerated. Aminoglycosides are rapidly removed from the body by hemodialysis.

Currently, aminoglycoside antibiotics are recommended to be administered 1 time per day at a dose calculated per kilogram of body weight. Prescribing drugs once a day, without affecting the therapeutic efficiency, can significantly reduce nephrotoxicity. For meningitis, sepsis, pneumonia and other severe infections, the maximum doses are prescribed, for diseases of the urinary tract - medium or minimum. In patients with renal insufficiency, the dose of aminoglycosides is reduced and the intervals between their administrations are lengthened.

The main routes of administration: intramuscularly, if the patient does not have serious hemodynamic disturbances; intravenously slowly or drip; topically (in the form of ointments and liniment); endotracheal instillations and inside.

The drugs do not penetrate into the cells. Easily pass through the placenta, enter the tissues of the inner ear and kidney cortex.

Aminoglycosides are not biotransformed.They are almost completely excreted by the kidneys unchanged. Effective in alkaline environments.

The main disadvantage This group is characterized by a rather high toxicity, their neurotoxic, first of all, ototoxic effect, manifested in the development of neuritis of the auditory nerve, as well as in imbalance, is especially pronounced. Severe hearing and balance disorders often lead to complete disability, and young children, having lost their hearing, often forget their speech and become deaf and dumb. Antibiotics-aminoglycosides can also have nephrotoxic effects. In this case, necrosis develops in the epithelium of the renal tubules, ending with the death of the patient.

When these antibiotics are taken orally, dyspeptic disorders are common. Anaphylactic shock is mainly caused by streptomycin sulfate, which in this respect is in second place after penicillin preparations.

Aminoglycosides can disturb hearing, balance (in 10 - 25% of patients), kidney function, and cause neuromuscular blockade. At the beginning of aminoglycoside therapy, tinnitus appears, the perception of high sounds outside the frequencies of spoken speech worsens, as the lesion progresses from the basal curl of the cochlea, where high-frequency sounds are perceived, to the apical part, which responds to low sounds. Aminoglycosides accumulate to a greater extent in the well-vascularized base of the cochlea. In severe cases, speech intelligibility is impaired, especially high-frequency whispering.

Headache precedes vestibular disorders within 1 - 2 days. In the acute stage, nausea, vomiting, dizziness, nystagmus, and postural instability occur. After 1 - 2 weeks. the acute stage turns into a chronic labyrinthitis (wobbly gait, difficulty in performing work). After another 2 months. the stage of compensation begins. The functions of the damaged vestibular analyzer are taken over by vision and deep proprioceptive sensitivity. Disorders in the motor sphere occur only with closed eyes.

As a result, aminoglycosides cause degeneration of the auditory nerve, death of hair cells in the spiral (Corti) organ of the cochlea and the ampulla of the semicircular canals. Auditory and vestibular disorders in the later stages are irreversible, since the sensitive cells of the inner ear do not regenerate.

The toxic effect of aminoglycosides on the inner ear is more pronounced in the elderly, potentiated by diuretics - ethacrine acid and furosemide. Streptomycin and gentamicin are more likely to cause vestibular disorders, neomycin, kanamycin and amikacin mainly impair hearing (in 25% of patients). Tobramycin damages the auditory and vestibular analyzers equally. Netilmicin is less dangerous, causing ototoxic complications in only 10% of patients.

In 8 - 26% of patients, aminoglycosides cause mild renal dysfunction after a few days of therapy. As antibiotics accumulate in the cortical layer of the kidneys, filtration and reabsorption deteriorate, proteinuria occurs, and enzymes of the brush border appear in the urine. Rarely, acute necrosis of the proximal renal tubules develops. Kidney damage can be reversible, since the nephrons are capable of regeneration.

It is less dangerous to administer antibiotics once a day with an intermittent course. Neomycin has a high nephrotoxicity (it is used exclusively locally), in order of decreasing pathogenic effect on the kidneys, tobramycin, gentamicin and streptomycin follow. The nephrotoxicity of aminoglycosides is enhanced by amphotericin B, vancomycin, cyclosporine, cisplatin, potent diuretics, and weakened by calcium ions. Against the background of kidney damage, the excretion of aminoglycosides decreases, which potentiates their oto- and vestibulotoxicity.

Against the background of anesthesia with the use of antidepolarizing muscle relaxants, aminoglycosides, independently causing neuromuscular blockade, can prolong the paralysis of the respiratory muscles. The most dangerous in this regard are injections of antibiotics into the pleural and peritoneal cavities, although the complication also develops when injected into the vein and muscles. Neomycin causes a pronounced neuromuscular blockade, kanamycin, amikacin, gentamicin, tobramycin and streptomycin are less toxic. The risk group is patients with myasthenia gravis and parkinsonism.

In neuromuscular synapses, aminoglycosides weaken the stimulating effect of calcium ions on the release of acetylcholine through the presynaptic membrane, reduce the sensitivity of nicotine-sensitive cholinergic receptors of the postsynaptic membrane. As antagonists, calcium chloride and anticholinesterase agents are injected into the vein.

Streptomycin can damage the optic nerve and narrow visual fields, as well as cause paresthesia and peripheral neuritis. Aminoglycosides have low allergenicity, only occasionally when they are administered, fever, eosinophilia, skin rash, angioedema, exfoliative dermatitis, stomatitis develop, anaphylactic shock develops.

Aminoglycosides are contraindicated in hypersensitivity, botulism, myasthenia gravis, Parkinson's disease, drug parkinsonism, hearing and balance disorders, and severe kidney disease. Their use during pregnancy is allowed only for health reasons. Breastfeeding is stopped for the duration of treatment.