Catad_tema Children's infections - articles

Antibacterial therapy of respiratory diseases in the outpatient practice of a pediatrician

ON THE. Korovina, A.L. Zaplatnikov, I.N. Zakharova

RATIONAL ETIOTROPIC THERAPY OF BACTERIAL INFECTIONS IN CHILDREN

Basic principles of rational antibacterial therapy

One of the main components of adequate etiopathogenetic treatment of bacterial infections, regardless of the severity and localization of the inflammatory process, is rational antibiotic therapy. The classic requirement for the choice of antibacterial therapy is the prescription of drugs in strict accordance with the antibiotic sensitivity of the pathogen. In addition, the ability of the antibacterial agent to penetrate into organs affected by infectious inflammation must be taken into account. This will allow us to assess the reality of creating effective therapeutic concentrations of the drug in the affected organs and tissues. Factors such as the epidemiological situation, the age of the child and his background pathology, as well as concomitant therapy, must be taken into account. Taking into account the age of the child, the diseases he suffers and the treatment carried out for this reason, will allow choosing from the entire arsenal of effective antibacterial agents those drugs whose use will not be accompanied by changes in pharmacokinetics and pharmacodynamics. This will help reduce the risk of developing side effects and unwanted effects of antibiotic therapy.

To choose the most effective drug from a large arsenal of modern antibacterial agents, it is necessary to take into account their degree of antimicrobial activity against specific pathogens. For objective comparative characterization of the antibacterial activity of various drugs in vitro, and, consequently, their supposed effectiveness against certain pathogens, standard methods are used. One of the main methods for microbiological testing of the sensitivity of pathogens to antibacterial agents is the determination of the minimum inhibitory concentration (MIC) of a pharmacological drug against a specific microorganism. Traditionally, the minimum inhibitory concentration of an antibacterial agent is determined, at which in vitro the growth of 90% of the strains of the identified pathogen is suppressed (MIC 90). MIC is the minimum inhibitory concentration at which 90% of pathogen strains are suppressed by an antimicrobial agent (in a microbiological study with a standard disk of this antimicrobial agent).

In subsequent sections of this manual, MIC 90 values ​​will be frequently encountered to characterize the antimicrobial activity of various antibacterial agents against specific pathogens. The authors consider it advisable to draw special attention of readers to the need for an independent comparative analysis of the values ​​of this indicator of various antibacterial drugs.

Rational antibacterial therapy is determined by a number of factors:

Nosological form of the infectious-inflammatory process;
- degree of sensitivity of the pathogen to antimicrobial agents;
- the degree of activity of the antimicrobial agent against a specific pathogen;
- the ability to achieve effective therapeutic concentrations of antimicrobial agents in damaged organs and tissues;
- knowledge of the characteristics of pharmacokinetics, pharmacodynamics and taking into account possible side effects of the selected drugs in children of different ages;
- the age of the child, his background pathology, as well as concomitant therapy.

Empirical choice of initial antibiotic therapy

Despite the fact that priority in the choice of antimicrobial therapy for infectious inflammation belongs to identifying the pathogen and determining its antibacterial sensitivity, outpatient doctors have to begin treatment of sick children more often without prospects for further verification of the etiological agent. The effectiveness of the choice of initial antibiotic therapy largely depends on the doctor’s knowledge of the epidemiological situation and likely potential pathogens that most often cause infectious processes of various localizations depending on the age of children. Knowledge and understanding of these points will improve the effectiveness of initial therapy. Empirical consideration of the above components will allow targeted antibacterial therapy to be carried out already at the first stage of treatment of a sick child (V.K. Tatochenko, 1996).

The choice of initial antibacterial therapy for infectious and inflammatory diseases in an outpatient setting is carried out empirically.

The empirical choice of initial antibacterial therapy is a choice that takes into account the antibacterial sensitivity of the suspected pathogens of a given nosological form of infection and world experience in the use of AB drugs for certain infectious and inflammatory diseases (N.V. Beloborodova, 1997).

The empirical choice of initial antibiotic therapy is not an intuitive choice, not at random. This is a choice based on convincing and reliable data on probable (potential) pathogens for various nosological forms of the infectious process in children of a certain age.

Thus, for the effective treatment of respiratory infectious diseases, the empirical choice of initial antibiotic therapy should take into account the location of the lesion, the likely pathogens and their potential sensitivity to antimicrobial agents. We will consider the etiological structure of acute respiratory diseases, the antibacterial sensitivity of pathogens of these infections and the tactics of empirical selection of etiotropic therapy in the following sections.

CLASSIFICATION OF CLINICAL FORMS OF ACUTE DISEASES OF THE RESPIRATORY TRACT IN CHILDREN

Timely diagnosis and rational therapy of various bronchopulmonary diseases requires the mandatory presence of a generally accepted classification, unified and very specific approaches to methodology and interpretation of the results of clinical and auxiliary research.

Conditional separation in the respiratory tract of the upper and lower sections is considered generally accepted (R.E. Berman et al., 1983; S.V. Rachinsky, V.K. Tatochenko, 1987). The pathological process during acute respiratory infection can involve both the upper and lower parts of the respiratory tract. At the same time, the degree of damaging effect of different parts of the respiratory tract, their clinical severity and significance differ significantly, which allows, with a certain degree of convention, to speak of predominant inflammation of the upper or lower respiratory tract.

Diseases of the upper respiratory tract include those nosological forms of respiratory pathology in which the localization of lesions is located above the larynx. Among the clinical forms of diseases of the upper respiratory tract, rhinitis, pharyngitis, nasopharyngitis, tonsillitis, sinusitis, laryngitis, and epiglotitis are distinguished. This group of diseases also includes acute otitis media. Among diseases of the lower respiratory tract, clinical forms such as tracheitis, tracheobronchitis, bronchitis and pneumonia are distinguished.

Agreed consensus provisions on the classification of the main clinical forms of bronchopulmonary diseases in children

In November 1995, at a joint meeting of a symposium of pediatric pulmonologists of Russia and the Problem Commission on Pediatric Pulmonology and Hereditary Lung Diseases of the Scientific Medical Council of the Ministry of Health of the Russian Federation, a new classification of nonspecific respiratory diseases was adopted, the main provisions of which are presented below.

Bronchitis (classification and diagnostic criteria)

Bronchitis is an inflammatory disease of the bronchi of various etiologies.

Criteria for diagnosing bronchitis: cough, dry and variable moist rales. An X-ray examination reveals the absence of infiltrative or focal changes in the lung tissue with possible 2-sided enhancement of the pulmonary pattern and the roots of the lung.

There are simple, obstructive and obliterating forms of acute bronchitis, recurrent (simple and obstructive) and chronic bronchitis.

Acute bronchitis (simple)- bronchitis occurring without signs of bronchial obstruction.

Acute obstructive bronchitis, bronchiolitis- acute bronchitis, occurring with signs of bronchial obstruction.

Diagnostic criteria: Obstructive bronchitis is characterized by the development of bronchial obstruction syndrome. Bronchiolitis is one of the clinical variants of acute obstructive bronchitis. Bronchiolitis is characterized by the development of more severe respiratory failure and an abundance of fine wheezing.

Acute obliterating bronchiolitis- a severe disease of viral or immunopathological origin, leading to obliteration of bronchioles and arterioles.

Recurrent bronchitis- bronchitis without obstruction, episodes of which are repeated 2-3 times over 1-2 years against the background of ARVI. Episodes of bronchitis are characterized by a duration of clinical symptoms of up to 2 weeks or more.

Recurrent obstructive bronchitis- obstructive bronchitis, episodes of which are repeated in young children against the background of ARVI. Unlike bronchial asthma, obstruction does not have a paroxysmal nature and is not associated with exposure to non-infectious allergens.

Chronical bronchitis- as an independent disease in children, it is rare; as a rule, it is a manifestation of other chronic diseases (cystic fibrosis, ciliary dyskinesia, and other chronic lung diseases).

Criteria for diagnosing chronic bronchitis- productive cough, variable moist rales in the lungs, heard for several months, 2-3 exacerbations per year with a total duration of the disease of at least 2 years.

Chronic bronchitis (with obliteration)- is the result of the consequences of acute obliterating bronchiolitis. McLeod syndrome (one-sided pulmonary “supertransparency”) is one of the variants of this disease.

Criteria for diagnosing chronic bronchitis (with obliteration)- respiratory failure of varying severity, persistent crepitus and fine bubbling moist rales in the lungs, increased transparency of the lung tissue during X-ray examination and a sharp decrease in pulmonary blood flow in the affected parts of the lungs during scintigraphic examination.

Pneumonia (classification and diagnostic criteria)

The uniform diagnostic criteria for pneumonia are the clinical picture and typical radiological signs. This approach to diagnosis was recognized by most researchers, supported by WHO specialists, and was adopted as the basis for the development of the X revision of the international classification of diseases and causes of death (ICD IX (1975) and X revisions (1992); WHO, 1990).

For morphological confirmation of the diagnosis of pneumonia, manifestations of acute infectious inflammation of the terminal respiratory sections of the lungs and the presence of exudate in the alveoli are mandatory.

Pneumonia is an acute infectious and inflammatory disease of the lungs with predominant damage to the respiratory sections and the obligatory presence of intra-alveolar exudation (ICD IX (1975) and X (1992)).

In clinical practice, for the diagnosis of pneumonia it is necessary to use the “gold standard” (S.V. Rachinsky, V.K. Tatochenko. 1987; WHO, 1990).

"Gold standard" for diagnosing pneumonia.

Pneumonia is an acute infectious and inflammatory disease of the lungs, diagnosed not only by the syndrome of respiratory distress and physical findings, but also by infiltrative, focal or segmental changes on an x-ray.

These diagnostic criteria make it possible to clearly distinguish pneumonia from many inflammatory diseases of the bronchopulmonary system, in which diffuse rather than focal or infiltrative changes in the lungs are detected on an x-ray (S.V. Rachinsky, V.K. Tatochenko, 1987).

Most researchers believe that the most optimal criterion for the classification of pneumonia should be the etiological principle of its construction. However, the lack of microbiological express diagnostics available for widespread practice does not allow a classification strictly based on the etiological factor. The results of multicenter epidemiological and microbiological studies to determine the etiology of respiratory infections made it possible to identify the most common pathogens of certain forms of pneumonia and the degree of their antibacterial resistance in various age and climatic geographic populations in children. This allows us to judge with a high degree of probability the most common potential pathogens, the degree of their antibiotic sensitivity, depending on the epidemiological characteristics and clinical variants of respiratory infections, including pneumonia. Thus, it was noted that the etiology of pneumonia depends on where and how the infection occurred, as well as on the age of the sick child. It is noted that under “home” (outpatient) conditions of infection, the most common etiological factors of pneumonia, depending on age, can be pneumococcus, Haemophilus influenzae, mycoplasma and moraxella. While in conditions of hospital (nosocomial) infection, the causative agents of pneumonia are often staphylococci and bacillary flora (Escherichia coli and Pseudomonas aeruginosa, Proteus, Klebsiella, etc.).

These factors are reflected in the new classification of pneumonia (Table 1).

Taking into account the presented epidemiological criteria for the classification of pneumonia, a doctor with a greater degree of confidence can empirically determine the range of the most likely causative agents of pneumonic infection. The latter allows you to rationally choose the initial etiotropic treatment and achieve a positive result of therapy, even in the absence of bacteriological control.

The pathogenesis and morphological picture of inflammation in focal, focal-confluent and segmental pneumonias are directly related to the primary infectious-inflammatory process in the bronchi. Therefore, focal, segmental and focal-confluent variants of inflammation of the lung tissue are classified as bronchopneumonia. These are the most common forms of pneumonia in childhood.

Lobar pneumonia is diagnosed in the presence of a typical clinical picture of pneumococcal pneumonia (acute onset with characteristic physical changes and cyclical course, rare tendency to destruction) and homogeneous lobar or sublobar infiltration on an x-ray. In young children, the typical clinical picture may be due to damage not to the entire lobe of the lung, but to only several segments (V.K. Tatochenko,

1987). Academician G.N. Speransky believed that the presence of a typical picture of lobar pneumonia in a young child is a reflection of the “degree of maturity of the response (resistance)” of his body. Currently, due to the widespread and timely use of antibacterial agents for respiratory infections, lobar pneumonia is a rare variant of infectious inflammation of the lung tissue (A.B. Kaukainen et al., 1990).

Table 1.
Classification of pneumonia (based on the results of a symposium of pediatric pulmonologists of Russia and a meeting of the Problem Commission on Pediatric Pulmonology and Hereditary Lung Diseases of the Scientific Medical Council of the Ministry of Health of the Russian Federation).

Depending on the conditions of infection: Community-acquired(“home”, outpatient). The most common pathogens: pneumococcus, Haemophilus influenzae, mycoplasma, moraxella. In-hospital(hospital, nosocomial). The most common pathogens: staphylococcus, Escherichia coli, Pseudomonas aeruginosa, Proteus, Serration, etc. Intrauterine.

Depending on the morphological changes: Bronchopneumonia: Focal; - segmental; - focal-confluent. Croupous. Interstitial.

Depending on the speed of resolution of the pneumonic process: Acute; Lingering.

IN depending on the nature of the flow: Uncomplicated; Complicated: pulmonary complications (pleurisy, destruction, abscess, pneumothorax, pyopneumothorax) extrapulmonary complications (infectious-toxic shock, disseminated intravascular coagulation syndrome, circulatory failure, adult-type respiratory distress).

Interstitial pneumonia is also a rare form of infectious-inflammatory lesion of the lungs. Interstitial pneumonia includes acute lesions of the lung tissue with predominant damage to the interstitium. As a rule, interstitial pneumonia is caused by pneumocysts, intracellular microorganisms and fungi.

Depending on the speed of resolution of the pneumonic process, acute and protracted course of pneumonia is distinguished. If the reverse development (resolution) of inflammatory changes in the lungs occurs within a period of up to 6 weeks, then the course of pneumonia is considered acute. Protracted pneumonia includes those forms in which the clinical and instrumental signs of the pneumonic process persist for 1.5 to 8 months from the onset of the disease.

ETIOLOGICAL STRUCTURE OF ACUTE INFECTIOUS DISEASES OF THE UPPER RESPIRATORY TRACT IN CHILDREN AND TACTICS FOR SELECTION OF RATIONAL ETIOTROPIC THERAPY

Etiological structure of acute infectious diseases of the upper respiratory tract in children

Among the etiological factors of acute infectious diseases of the upper respiratory tract, the leading place (in 95% of cases) is occupied by viruses (V.K. Tatochenko, 1987). At the same time, among acute respiratory viral infections (ARVI) in children, diseases of non-influenza etiology predominate (WHO, 1980). The most common cause of ARVI in children, especially young children, is respiratory syncytial virus (PC virus) (I Orstavik et al., 1984). Mycoplasma infection is associated with up to 6-10% of cases of acute respiratory diseases in children. The epidemic nature of respiratory mycoplasmosis has been noted with an interval of 4-8 years without a clearly defined seasonality and connection with climatogeographic zones (R.A. Broughton, 1986; G. Peter et al., 1994).

The tropism of viral pathogens to certain parts of the respiratory tract has been established. Thus, rhinoviruses and coronaviruses more often cause the “common cold” in the form of rhinitis and nasopharyngitis (V.K. Tatochenko, 1987; N.E. Kaue et al., 1971; J.P. Fox et al., 1975). Coxsackie viruses also more often cause acute diseases of the nasopharynx, while parainfluenza viruses are responsible for the development of stenosing laryngitis and tracheobronchitis, and the vast majority of cases of pharyngoconjunctivitis are caused by adenovirus infection (R.E. Berman, V.C. Vaughan, 1984).

It has been established that among acute respiratory infections, especially in children attending child care institutions, mixed viral-viral infections account for a high proportion - up to 7-35% (S.G. Cheshik et al., 1980). It should also be noted that among acute respiratory infections there are both isolated bacterial and mixed viral-bacterial lesions. The latter are associated with the activation of microbial autoflora due to disruption of the barrier function of the respiratory tract and a decrease in the body's defenses, as well as superinfection with bacterial agents. The addition of a bacterial infection leads to an increase in the severity of the disease and may be the main reason for the unfavorable outcome of the disease. At the same time, there are also primary bacterial lesions of the upper respiratory tract. Thus, acute pharyngitis, follicular and lacunar tonsillitis in more than 15% of cases are caused by isolated exposure to group A beta-hemolytic streptococcus. Acute purulent otitis media and sinusitis are mainly caused by pneumococcus, Haemophilus influenzae, Moraxella catarrhalis and pyogenic streptococcus (E.R. Wald, 1992; C. D. Bluestone et al., 1994). Bullous inflammation of the tympanic septum (myringitis) is associated with mycoplasma infection. The etiological role of Haemophilus influenzae (type B) in the development of acute epiglotitis has been proven. The presented data on the most common bacterial pathogens of acute respiratory infections of the upper respiratory tract are summarized and presented in table form (Table 2).

Tactics for choosing rational etiotropic therapy for acute infectious diseases of the upper respiratory tract in children

Unfortunately, to date there is no unified approach to the etiotropic treatment of respiratory viral infections in children. Drugs such as amantadine and rimantadine, successfully used in the treatment of influenza (especially effective against strain A 2) in adults, are officially approved in pediatric practice only for children over 7 years of age. The use of ribavirin, an effective viricidal drug against RS infection and influenza viruses, is possible only in a hospital with a specialized intensive care unit.

Since the late 70s of this century, leukocyte interferon for intranasal or inhalation use has been widely used for the prevention and treatment of initial manifestations of ARVI in children (A.B. Kornienko et al., 1980; L.V. Feklisova et al., 1982 and etc.). In recent years, recombinant interferon alpha-2b for rectal use (Viferon) has appeared on the domestic pharmaceutical market, which potentially expands therapeutic options in the treatment of ARVI in children.

Table 2.
The main bacterial pathogens of acute diseases of the upper respiratory tract in children.

Empirical choice of initial etiotropic therapy for acute bacterial diseases of the upper respiratory tract in children

Certain forms of respiratory infections (tonsillitis, pharyngitis, purulent sinusitis and otitis) or the development of bacterial complications of ARVI require mandatory and timely inclusion of antibacterial therapy in the complex of treatment measures. Timely and adequate etiotropic therapy for tonsillitis, pharyngitis and exacerbation of chronic tonsillitis in children with a hereditary predisposition to rheumatic diseases can reduce the risk of developing rheumatism (N.A. Belokon, 1987). A rational choice of initial antibiotic therapy for purulent sinusitis and otitis media allows one to prevent such serious complications as mastoiditis, bacteremia and meningitis (G.S. Giebink et al., 1991).

The basic principles of selection and tactics of initial antibiotic therapy in the treatment of bacterial infections of the upper respiratory tract in children are presented in Table 3.

It should be noted that the choice of initial etiotropic therapy may vary depending on epidemiological features, the nature of the pathogen, the clinical form of the disease and the background conditions of the child. Table 3 summarizes the generally accepted, consensual provisions on rational

Table 3.
Principles of selection and tactics of initial etiotropic therapy for mild and moderate clinical forms of bacterial infections of the upper respiratory tract in children

Clinical options	Main pathogens	Drugs of choice	Alternative drugs
Pharyngitis	Streptococcus pyogenes (p-hemolyt. Group A)
Angina	Streptococcus pyogenes (|3-hemolyt. Group A)	Natural Penicillin (Oral Forms)	If you are allergic to beta-l actinic AB: macrolides or TMP/SM
Sinusitis	Streptococcus pneumoniae; Haemophilus Influenzae; Moraxella; catarrhalis.
Acute otitis media	Streptococcus pneumoniae; Haemophilus Influenzae; Moraxella catarrhalis.	“Protected” semi-synthetic penicillins (Oral forms) or cephalosporins 2P (Oral forms)	For allergies to beta-lactam ABs: TMP/SM or macrolides + sulfisoxazole

It should be noted that the choice of initial etiotropic therapy may vary depending on epidemiological features, the nature of the pathogen, the clinical form of the disease and the background conditions of the child. Table 3 summarizes the generally accepted, consensus provisions for rational antibiotic therapy for upper respiratory tract infections. The column “drugs of choice” indicates antibacterial agents, the use of which is most rational for these clinical variants of respiratory infections. The column “alternative drugs” presents antibacterial drugs that can be considered as “starter” for the specified nosological forms, if taking the “drugs of choice” is impossible for some reason (intolerance, allergy to medications of this group, unavailable in the pharmacy chain, etc. ).

Antibacterial therapy for tonsillitis and pharyngitis in children on an outpatient basis The empirical choice of initial etiotropic therapy for bacterial inflammation of the upper respiratory tract, as well as other infectious respiratory diseases in children, is based on reliable data from multicenter population studies to determine the main microbial pathogens and their resistance to antibacterial drugs.

Group A beta-hemolytic streptococcus, the main causative agent of sore throats and pharyngitis, continues to remain highly sensitive to natural beta-lactam antibiotics. This allows us to recommend natural penicillins as the drugs of choice for these diseases and for exacerbation of chronic tonsillitis. In this case, in mild and moderate cases, it is advisable to prescribe penicillins for oral administration. A contraindication to the prescription of penicillins is anamnestic evidence of allergic reactions to beta-lactam antibiotics (to all, not just penicillins). In this case, the drugs of choice are macrolides and biseptol (trimethoprim/sulfamethoxazole (TMP/SM)).

Table 4 presents the tactics of initial etiotropic therapy for mild and moderate forms of pharyngitis and tonsillitis in children. The main groups of drugs are indicated in large, underlined font. The international names of some of the most typical drugs from each group of antibacterial agents presented are also indicated. International names of active substances are presented in italics. Dosages and methods of administration are given below the international names of the drugs. In brackets, under the name of the pharmacological group (in small italics), are the trade names of some of the most commonly used drugs.

Antibacterial therapy for sinusitis and acute otitis media in children.

The data on the development of antibiotic resistance of the main pathogens of purulent sinusitis and otitis media (pneumococcus, Haemophilus influenzae and Moraxella) look alarming (J.O. Klein., 1993; R. Cohen, 1997). Reports that appeared in the early 80s of this century about an increase in the frequency of isolation of penicillin-resistant strains of Streptococcus pneumoniae were subsequently confirmed by a decrease in the clinical effectiveness of traditionally used penicillins, macrolides and sulfonamides for pneumococcal infections (K.R. Klugman et al., 1986; Wust J et al., 1987, etc.). The rate of increase in antibiotic resistance in the main pathogens of bacterial respiratory tract infections in children is especially alarming. Thus, over a 10-year period (from 1984 to 1994) in the Scandinavian countries, Great Britain, Spain, and France, an increase in the proportion of penicillin-resistant pneumococcal strains was noted from 1.5-3% to 32-55% (P. Geslin, 1995 ; R. Cohen, 1997). It has also been established that more than 90% of Moraxella strains and more than 20% of Haemophilus influenzae strains produce beta-lactamase (penicillinase). Table 5 presents summarized data on the frequency of isolation of beta-lactamase-producing strains among the main causative agents of bacterial infections of the upper respiratory tract in children.

Table 4.
Initial etiotropic therapy of mild and moderate forms of pharyngitis and tonsillitis in children (AB drugs for oral use)

Clinical options	Main pathogens	Drugs of choice	Alternative drugs
Pharyngitis	Streptococcus	Natural	Macrolides*.
Angina	pyogenes	penicillins	(erythromycin, macro-
	(P-hemolyt.	(V-penicillin,	pen, klacid, sumamed,
	Group A)	smallpox, cleacyl,	rulid).
		megacillin-oral,	Erythromycin**
		phenoxymethyl peni-	Daily dose: 30-50
		cillin)	mg/kg,
		Phenoxy methyl l peni-	Multiplicity - 4 rubles. per day
		cillin Daily	Course - 7-10 days.
		dose: up to 1 0 years - 50-	Midecamycin
		100 thousand units/kg,	Daily dose 30-50
		over 10 years old - 3	mg/kg, Multiplicity 2-3 r.
		million units per day.	per day. Course 7-10
		Frequency of reception	days or
		4-6 times a day for 1	TPM/SM (Biseptol).
		an hour before meals or 2 hours	Daily dose: 6-8
		hours after eating.	mg/kg by TMP.
		Course 5-10 days.	Multiplicity of reception - 2
			once a day. TO
			Course - 5-6 days

* drugs representing macrolides in the table are selected as the most characteristic for different chemical subgroups (14; 15; 16 members) of macrolide antibiotics;
** - erythromycin, due to the currently available “new” macrolide drugs, which are less likely to cause side effects, is not recommended for use in infants and preschool children.

The data presented in Tables 2 and 5 must be taken into account when initially choosing antibacterial therapy for acute otitis media and sinusitis. In this case, the choice should be made in favor of drugs with a wide spectrum of antibacterial action (the ability to suppress both gram-positive - pneumococcus and streptococcus pyogenes, and gram-negative pathogens - Haemophilus influenzae and Moraxella), and that are resistant to the effects of bacterial beta-pactamase. Therefore, it is considered justified to include semisynthetic penicillins, “protected” from the inhibitory effects of beta-lactamases and 2nd generation cephalosporins, as first-line drugs (drugs of choice) for the treatment of acute otitis media and sinusitis. At the same time, highly effective forms of antibacterial drugs for oral administration have recently appeared in the arsenal of practicing doctors. They should be given preference in the treatment of mild and moderate forms of sinusitis and acute otitis media on an outpatient basis.

Table 5.
Frequency of isolation of beta-lactamase-producing strains among the main causative agents of bacterial infections of the upper respiratory tract in children (%)*

* - filed by Red Book, 1994: J.P. Sanford, 1994; P. Geslin. 1995; R. Cohen. 1997.

Among the oral forms of “protected” semi-synthetic penicillins, it is more rational to use those combinations that include amoxicillin. Amoxicillin is an active metabolite of ampicillin with the same spectrum of antibacterial action, but is much more active than its predecessor - 5-7 times (Yu.B. Belousov, V.V. Omelyanovsky, 1996; J.O. Klein., 1993). The advantages of amoxicillin over ampicillin are summarized in Table 6.

Table 6.
Comparative characteristics of amoxicillin and ampicillin*

* - adapted from “Clinical pharmacology of respiratory diseases” (Yu.B. Belousov, V.V. Omelyanovsky, 1996).

The use of a combination of amoxicillin with substances that “protect” it from the inhibitory effect of bacterial beta-lactamases can significantly expand the spectrum of the antibacterial action of the drug. This is due to the fact that amoxicillin, “protected” from the effects of bacterial enzymes, retains bactericidal activity against penicillin-resistant strains. Considering the data on the frequency of detection of beta-lactamase-producing strains among the main pathogens of respiratory infections in children (Table 5), the practical significance of the use of “protected” penicillins becomes clear. Clavulanic acid and sulbactam are used to “protect” semisynthetic penicillins from the inhibitory effect of beta-l actamase. The most commonly used combination is amoxicillin with clavulanic acid (augmentin, amoxiclav, clavocin, moxiclav) and ampicillin with sulbactam (sulbacin, unazine). Less commonly, a combination of two semi-synthetic penicillins is used, one of which is resist-tent to kbeta-lactamase (ampicillin + oxacillin (Ampiox) or amoxicillin + cloxacillin (Clonac-x)).

Oral forms of 2nd generation cephalosporins (CP-2p) can also be used as the drugs of choice. The latter have a bactericidal effect on the main pathogens of respiratory infections. Compared to 1st generation cephalosporins, they are significantly more active against pneumococci and Haemophilus influenzae, are more resistant to the effects of p-lactamase and have good bioavailability (Yu.B. Belousov, V.V. Omelyanovsky, 1996; S. V. Sidorenko, 1997). Among this group of antibacterial drugs, cefuroxime axetil (zinnate and analogues) and cefaclor (ceclor and its analogues) deserve attention. It is worth noting that cefuroxime, compared to cefaclor, has more pronounced activity against the main pathogens of infections of the upper respiratory tract, including penicillin- and ampicillin-resistant strains (J. Bauenrfiend, 1990). At the same time, when using cefaclor, adverse events in the form of dyspepsia are less common (W. Feldman et al., 1990). When using cefuroxime in the treatment of severe forms of the disease, you can use the so-called “stepped” (staged) therapy. Moreover, during the period of severe toxicosis, cefuroxime is prescribed parenterally (zinacef), and when the intensity of infectious and inflammatory manifestations decreases, therapy continues with the oral form of the drug (zinnat). It should be noted that although some authors recommend using cefuroxime as an alternative to penicillins if you are allergic to them (Yu.B. Belousov, V.V. Omelyanovsky, 1996), in some cases, the development of cross-allergy is still possible (J.P. Sanford , 1994).

In cases where the use of (5-lactam antibiotics as “drugs of choice” is contraindicated (intolerance, allergy to medications in this group, cross-allergy to beta-l acta derivatives, etc.) or is impossible for some other reason, starting Therapy for sinusitis and acute otitis media can begin with biseptol (TMP/SM) or, less rationally, with a combination of macrolides with sulfisoxazole (Table 3).

Table 7 presents data on the choice and characteristics of initial antibiotic therapy for mild and moderate forms of sinusitis and acute otitis media in children.

Table 7.
Tactics for choosing initial etiotropic therapy for mild and moderate forms of sinusitis and acute otitis media in children (oral forms of AB drugs)*

CLINICAL options	Main pathogens	Drugs of choice	Alternative drugs
Sinusitis	Streptococcus	Amoxicillin +	If you are allergic to
Spicy	pneumoniae-	clavulanic acid	beta-lactam
average	Haemophilus	Daily dose: (calculation according to	AB: TMP/SM
otitis	influenzae	amoxicillin): - up to 2	(Biseptol)
	Moraxella	years - 20 mg/kg, 2-5 years - 375	Daily dose
	catarralis	mg/day, 5-1 Oleg -750 mg/day,	6-8 mg/kg
		>10 years - 750 mg - 1 g / day.	TMP.
		Frequency of intake is 3 rubles. d.	Multiplicity
		Course 5-14 days or	taking 2 times a day
		Cefuroxime axetil	days
		Daily dose: up to 2 years -	Course 5-6 days
		250 mg/day, > 2 years - 500	or
		mg/kg. Multiplicity of reception 2	Macrolides +
		R. in the village Course 7 days or	Sulfixazole
		Cefaclor
		Daily dose: 20-40 mg/kg.
		Frequency rate: 2 rubles. V
		day. Course 7 days.

Treatment of mild and moderate forms of infectious diseases of the upper respiratory tract can be carried out on an outpatient basis. In this case, preference should be given to oral forms of antibacterial drugs. The latter is associated with high efficiency, good bioavailability and tolerability, rare development of undesirable effects and adequate compliance of modern antibacterial drugs. Children with severe clinical variants of respiratory infections should be treated in a hospital setting. The choice of etiotropic therapy is determined depending on the clinical and epidemiological features of the disease and with mandatory consideration of outpatient antibacterial treatment.

The principles and tactics of etiotropic therapy for bacterial infections of the upper respiratory tract in children outlined in this section and summarized in table form (Table 3) are generally accepted. At the same time, new and promising drugs are emerging, which are not yet widely known, for the treatment of bacterial infections of the respiratory tract. An example is the bacteriostatic antibiotic fusafungin, which in the form of a monodisperse non-hygroscopic aerosol form (bioparox) is successfully used for the local treatment of pharyngitis, exacerbation of chronic tonsillitis and rhinitis in children (G.L. Balyasinskaya, 1998).

ETIOLOGICAL STRUCTURE OF ACUTE INFECTIOUS DISEASES OF THE LOWER RESPIRATORY TRACT IN CHILDREN AND TACTICS FOR SELECTION OF RATIONAL ETIOTROPIC THERAPY

Etiology of “domestic” infectious diseases of the lower respiratory tract in children

Among diseases of the lower respiratory tract, clinical forms such as tracheitis, tracheobronchitis, bronchitis and pneumonia are distinguished.

The etiological factors of lower respiratory tract infections are often viral-viral and viral-bacterial associations, as well as fungal and intracellular pathogens. Viral infection is the most common cause of tracheitis, tracheobronchitis and bronchitis. While pneumonia is more typical of a mixed viral-bacterial infection. At the same time, the “triggering” role of viral agents in the pathogenesis of pneumonia is considered indisputable and has long been proven (Yu.F. Dombrovskaya, 1951; N.A. Maksimovich, 1959; M.E. Sukhareva, 1962, etc.). Activation of the bacterial flora and superinfection during ARVI are associated with disruption of the barrier function of the respiratory tract and a decrease in the body's resistance (S.G. Cheshik et al., 1980). Viral agents, violating the integrity and functional activity of the ciliary epithelium and alveolar barrier, lead to the “exposure” of receptors of the cells of the basal layer of mucous membranes and inhibition of local immunity factors of the respiratory tract (V.V. Botvinyeva, 1982; V.K. Tatochenko, 1987 and 1994) . At the same time, there is a decrease in functional activity and an imbalance of systemic immunity (inhibition of the T-cell link, disimmunoglobulinemia, high sensitization of leukocytes to bacterial and mycoplasma antigens, perversion of phagocytic functions, etc.) (O.I. Pikuza et al., 1980; L.V. Feklisova et al., 1982; V.P. Buiko, 1984; R.C. Welliver et al., 1982). All this creates the preconditions for superinfection or activation of pneumotropic autoflora and the development of bacterial complications of the current ARVI. At the same time, tracheobronchitis and bronchitis, complicated by the addition of bacterial flora, clinically occur more severely and for a long time. Bacterial tracheobronchitis and bronchitis in outpatient settings are most often caused by pneumococci and other streptococci, as well as Haemophilus influenzae and Moraxella. In recent years, the importance of intracellular pathogens (chlamydia, mycoplasma, legionella) in the development of infections of the lower respiratory tract has increased (G.A. Samsygina et al., 1996).

Indications for X-ray examination of children suffering from acute respiratory diseases

The inclusion of mandatory x-ray confirmation of pneumonia in the “gold standard” of diagnosis makes it possible to diagnose the disease at the early stages of the pathological process and, by promptly prescribing targeted etiopathogenetic therapy, significantly improve its prognosis. If the development of pneumonia is suspected in children suffering from acute respiratory infections, an X-ray examination of the chest organs is indicated.

Indications for X-ray examination

An indication for prescribing an X-ray examination should be the presence of at least one of the following factors: a child with a cough and fever for 2-3 days;

Dyspnea;
- cyanosis;
- severe symptoms of intoxication;
- typical auscultatory or percussion changes (especially asymmetrical localization).

Antibacterial therapy of lower respiratory tract infections in children

In the vast majority of cases, acute bronchitis in children has a viral etiology. Therefore, as a rule, antibacterial therapy is not indicated for the treatment of uncomplicated forms of respiratory infections of the lower respiratory tract. Prophylactic administration of antibiotics for ARVI with symptoms of bronchitis does not reduce the duration of the disease and does not reduce the frequency of bacterial complications (R.E. Behrman, 1983). The use of only symptomatic drugs in the treatment of children with uncomplicated forms of acute bronchitis is accompanied by high therapeutic effectiveness (V.K. Tatochenko et al., 1984).

Antibacterial therapy for respiratory infections of the lower respiratory tract in children is indicated only if they simultaneously have foci of bacterial inflammation (purulent otitis, sinusitis, tonsillitis), severe symptoms of intoxication, prolonged - more than 2-3 days - febrile fever, as well as hematological changes (neutrophilic leukocytosis) that do not allow excluding the bacterial genesis of the disease. G.A. Samsygina (1997) believes that in young children antibacterial drugs should also be used in the complex treatment of obstructive syndrome. Strict adherence to the above indications will dramatically reduce the unjustified use of antibacterial agents for uncomplicated forms of acute bronchitis in children. The latter is very important, since one of the reasons for the increase in antibiotic resistance in bacteria is the widespread and uncontrolled use of antibiotics in acute respiratory infections. Thus, a strictly justified reduction in the use of antibacterial drugs in uncomplicated forms of acute bronchitis will reduce the frequency of development of antibiotic-resistant strains of the main pneumotropic pathogens.

In cases where there are indications for prescribing antibacterial therapy, the choice of starting drug should be made based on the expected etiology of the pathogen. Bacterial tracheobronchitis and bronchitis at home are most often caused by streptococci (mainly pneumococcus), Haemophilus influenzae and Moraxella. Considering the significant frequency of beta-lactamase-producing strains among these pathogens (Table 5), it is advisable to use “protected” penicillins, 2nd generation cephalosporins, TMP/SM as initial therapy.

One should also take into account the increasing role of intracellular pathogens (mycoplasma, chlamydia, etc.) in the etiology of infections of the lower respiratory tract. The lack of a therapeutic effect from the use of initial antibiotic therapy for 2-3 days may be due to atypical pathogens. In this case, macrolides should be considered the drugs of choice. When deciding to use macrolides in young children, preference is given to semi-synthetic 14-member (roxithromycin, clarithromycin, etc.), 15-member (azithromycin) and 16-member

In children aged from 3-6 months to 5 years of life, “domestic” pneumonia is most often caused by pneumococcus and Haemophilus influenzae. Whereas in children over 5 years of age, the main pathogens are pneumococcus, mycoplasma and, less commonly, Haemophilus influenzae (Table 9).

Recent years have been characterized by an increased role of intracellular pathogens in the development of ambulatory pneumonia. At the 7th European Congress of Clinical Microbiology and Infectious Diseases (1995), special attention was paid to the problem of mycoplasma pneumonia in children who became ill at home. In a prospective study of children with community-acquired pneumonia, it was found that the most common cause of infectious pneumonia in older schoolchildren, in addition to pneumococcus, is mycoplasma (up to 40%). Several studies presented at the congress focused on the occurrence of mycoplasma pneumonia in children under 5 years of age. This fact deserves close attention, since it was previously believed that mycoplasma is an extremely rare causative agent of pneumonia in children of early and preschool age (up to 2%) (N.M. Foy et al., 1979).

Changes in the etiological structure of pneumonia due to an increase in the proportion of intracellular pathogens (mycoplasma, chlamydia, etc.) require changes in the strategy and tactics of etiotropic therapy.

Tactics of antibacterial therapy for “domestic” pneumonia in children

Timely and targeted etiotropic treatment of pneumonia largely determines the prognosis of the disease. However, in an outpatient setting, bacteriological rapid diagnostics will obviously remain a problematic research method for many years to come. Therefore, the doctor, when empirically choosing initial antibacterial therapy, must take into account, depending on age and epidemiological situation, potential pathogens and their sensitivity to antimicrobial agents.

Table 9.
Etiological structure of extraneoplastic pneumonia in children depending on age (generalized data)

Taking into account that the etiological structure of pneumonia in children of different ages has its own characteristics, it is advisable to consider the tactics of choosing initial antibiotic therapy separately for each age group.

The choice of initial antibiotic therapy for home pneumonia in children aged 6 months to 5 years

In newborns and children in the first six months of life, pneumonia is more common in premature infants, in children who have undergone intrapartum aspiration, asphyxia, tracheal intubation and artificial ventilation and other pathological conditions of the neonatal period that required treatment with broad-spectrum antibiotics and prolonged stay in medical institutions. The latter determines the characteristics of infection in this category of children. In addition to infection by the flora of the birth canal, contamination with hospital strains of microorganisms, often polyresistant to antibacterial agents, is added. Features of the etiological structure of pneumonia in these children is the breadth of the spectrum of causally significant microbial pathogens (group B and D streptococci, staphylococci, bacillary flora, viruses, intracellular pathogens, etc.).

The development of pneumonia in children in the first weeks and months of life almost always requires observation and treatment in a hospital setting. Mandatory hospitalization of children in this age group with pneumonia is associated with the need for constant dynamic monitoring of their clinical condition. This is due to the high risk of rapid progression of pneumonia and the development of complications in children in the first months of life. The latter is associated with the characteristics of their infection, morphofunctional status and transient immaturity of organs and systems.

It should be emphasized once again that treatment of children with pneumonia in the first weeks and months of life should be carried out in a hospital setting. In this case, etiotropic therapy is carried out with broad-spectrum antibacterial drugs. The basic principles and features of the treatment of children with pneumonia in this age category, as well as the tactics for choosing the starting combination of antibacterial drugs, require special and separate analysis, which is not included in the scope of issues covered in this guide. For an in-depth and detailed study of this problem, you should refer to the monographs “Antibiotics and vitamins in the treatment of newborns” by N.P. Shabalov, I.V. Markova, 1993) and “Pneumonia in Children” (edited by Prof. Kaganov S.Yu. and Academician Veltishchev Yu.E., 1995).

“Domestic” pneumonia in children of early and preschool age is most often caused by pneumococcus and Haemophilus influenzae. Moreover, up to 1/3 of the strains of these pathogens produce (5-lactamases and, therefore, are resistant to natural and semi-synthetic penicillins. Therefore, suspecting pneumococcus or Haemophilus influenzae as etiological factors of pneumonia, it is advisable to prescribe those antibacterial drugs that are not destroyed (3 -lactamases (“protected” penicillins, second-generation cephalosporins, biseptol (TMP/SM)).

The main causative agents of “domestic” (community-acquired) pneumonia in children aged 6 months to 5 years: Streptococcus pneumoniae, Haemophilus influenzae.

It should also be noted that there is a tendency towards an increase in the etiological role of mycoplasma V development of domestic pneumonia in children aged 6 months to 5 years. Clinical differences in mycoplasma pneumonia are nonspecific. Mycoplasma genesis of pneumonia can be suspected through a comprehensive analysis of the clinical (persistent low-grade fever, persistent cough, absence of typical pneumonic equivalents during physical examination) and radiological (heterogeneous infiltration, usually 2-sided, asymmetrical, pronounced vascular-interstitial component) picture of the disease, as well as lack of therapeutic effect within 2-3 days from initial antibacterial therapy with beta-lactam antibiotics (penicillins or cephalosporins). In these clinical situations, it is advisable to switch to therapy with macrolides, which are highly active against intracellular pathogens, including mycoplasma.

Particular attention should be paid to the fact that the recent frequent, and not always justified, use of macrolides in the form of starting therapy is accompanied by the emergence of resistant strains of microorganisms. Thus, it was noted that penicillin-resistant pneumococcal strains in 41% of cases are resistant to 14- and 15-membered macrolides (erythromycin, roxithromycin, clarithromycin, azithromycin) (J. Hofman et al., 1995). To a lesser extent, this applies to 16-membered macrolides (spiramycin, dzosamicin) (K. Klugman, W. Moser, 1996). At the same time, a decrease in the frequency of use of macrolides leads to the restoration of the sensitivity of pathogens to antibiotics of this group (L.S. Strachunsky, S.N. Kozlov, 1998). Obviously, taking into account the above data will reduce the uncontrolled prescription of macrolides. Moreover, in case of intolerance to 3-lactam antibiotics and the absence of data in favor of the mycoplasma genesis of the disease, biseptol (TMP/SM) should be considered the drug of choice for mild and moderate forms of domestic pneumonia.

Etiotropic treatment of children with mild and moderate clinical variants of pneumonia can be carried out with oral forms of antibacterial drugs. As a rule, with the right choice of drug, a positive clinical effect (normalization of body temperature, reduction of manifestations of intoxication, reverse development of physical symptoms) is observed within the same time frame as with parenteral administration of antibiotics (V.K. Tatochenko, 1994). Convincing data have been obtained on the possibility of widespread use of oral forms of antibiotics for the treatment of uncomplicated forms of pneumonia, not only of mycoplasma and chlamydial etiology, but also caused by other pneumotropic pathogens (A.M. Fedorov et al, 1991). For moderate forms of pneumonia with severe manifestations of intoxication and febrile fever, it is advisable carrying out "stepwise" (staged) etiotropic therapy (GA. Samsygina, 1998). In this case, the drugs of choice for parenteral administration of antibiotics are cefuroxime (Zinacef) or a combination of ampicillin with sulbactam (Unasin). After 2-3 days, with a decrease in the symptoms of intoxication and relief of fever, a transition is made to oral forms of the corresponding drugs:

Zinacef (cefuroxime for parenteral administration) 60-100 mg/kg/day - in 3 intramuscular injections,
- zinnat (oral cefuroxime).

Children under 2 years old - 125 mg 2 times a day. Children over 2 years old - 250 mg 2 times a day. or

Unazine (ampicillin + sulbactam) for parenteral administration 150 mg/kg/day in 3 intramuscular injections,
- unasin (ampicillin + sulbactam) for oral administration. Children weighing less than 30 kg - 25-50 mg/kg/day in 2 divided doses. Children weighing more than 30 kg - 375-750 mg/day in 2 divided doses.

Table 10 presents the tactics for choosing empirical starting antibacterial therapy for “domestic” pneumonia in children aged 6 months to 5 years.

Treatment of mild and moderate forms of pneumonia in young children can be carried out on an outpatient basis only if it is possible to dynamically monitor the child’s condition (daily until body temperature normalizes and symptoms of intoxication are relieved), additional therapeutic and diagnostic measures are carried out, as required by the instructions for creation of a “hospital at home”. Social conditions and the general cultural and educational level of parents or relatives caring for the child must be taken into account. If it is impossible to create a “hospital at home”, or the low cultural level of the parents, as well as unfavorable social and living conditions, the child must be hospitalized.

Tactically correct, it should be considered mandatory to hospitalize a child with severe symptoms of infectious toxicosis and manifestations of pulmonary heart failure, regardless of age, form of respiratory disease and social and living conditions.

The choice of initial antibiotic therapy for “domestic” pneumonia in children over 5 years of age

Analysis of the results of numerous studies to clarify the etiology of acute infections of the lower respiratory tract (Table 9) allows us to conclude that in children over 5 years of age the main causative agents of pneumonia are pneumococcus, mycoplasma and Haemophilus influenzae.

Table 10.
Initial etiotropic therapy of mild and moderately severe forms of “domestic” neumonia in children aged 6 months to 5 years

The main causative agents of “domestic” (community-acquired) pneumonia in children over 5 years of age:

Streptococcus pneumoniae,
Mycoplasma pneumoniae
Haemophilus influenzae.

Expanding the range of potential pathogens of pneumotropic infection due to the greater etiological significance of mycoplasma in this age group requires the inclusion of macrolides in the initial antibacterial therapy as the drugs of choice (Table 11). At the same time, the appearance on the domestic pharmaceutical market of a macrolide drug with special pharmacokinetic properties (azithromycin) makes it possible to carry out antibacterial therapy for mild and moderate “domestic” pneumonia in a short (3-5-day) course ((L.S. Strachunsky et al., 1998; N. Principi et al., 1994; J. Harris et al., 1996) This allows to increase compliance with therapy, reduce the total dose of the drug and the risk of adverse drug reactions, and also reduce the cost of treatment (L.S. Strachunsky and al., 1998). Discontinuation of azithromycin on days 3-5 from the start of therapy, when physical manifestations of the disease still persist, should not mislead that etiotropic therapy for pneumonia has been discontinued. Features of the pharmacokinetics of azithromycin are its ability to accumulate and remain in high concentration for a long time in tissues, providing a long-lasting antibacterial effect (J. Williams et al., 1993).Therefore, after discontinuation of the drug, even with a 3-day course of treatment, the antibacterial effect of azithromycin in tissues continues for another 5-7 days (G. Foulds et al., 1993).

Treatment of children with mild and moderate pneumonia, without significant manifestations of intoxication and febrile fever, is carried out with oral forms of antibacterial drugs. In cases where a moderate form of pneumonia is accompanied by severe symptoms of intoxication and febrile fever, it is advisable to begin therapy with parenteral administration of antibiotics (2nd generation cephalosporins (zinacef) or “protected” semi-synthetic penicillins (unasin)) followed by switching to oral administration. Thus, with the improvement of the child’s condition, a decrease in the manifestations of intoxication, and a tendency towards normalization of body temperature, a transition to therapy with oral forms of the appropriate antibiotics is carried out (zinacef is replaced by zinnat, and unasin for parenteral administration is replaced by unasin for oral administration).

Evaluation of the effectiveness and duration of antibacterial therapy for “domestic” pneumonia

The empirical choice of initial antibacterial therapy, unfortunately, does not always allow precise and targeted action on the etiologically significant microbial agent. It is very important to promptly assess whether the selected antibacterial agent has an inhibitory effect on the causative agent of pneumonia. The adequacy of the choice of initial antibacterial therapy is assessed primarily by the dynamics of the temperature reaction and the reduction in the manifestations of intoxication. Clinical criteria for the effectiveness of an antibacterial drug for pneumonia are a decrease in body temperature to normal or low-grade levels, improvement in well-being, appearance of appetite, decrease in respiratory rate and pulse during the first 24-48 hours of treatment (A.A. Arova, 1988). If fever and symptoms of intoxication persist during treatment with an antibacterial drug for 36-48 hours, one should conclude that there is no effect from the therapy and change the antibacterial drug to an alternative one (V.K. Tatochenko, 1987).

The vector of action of antibacterial agents is aimed at pathogens of the infectious process. Antibacterial agents do not have a direct effect on the processes of normalization of morpho-functional changes that have developed as a result of an infectious-inflammatory process in the lungs. Therefore, the duration of antibacterial therapy is determined by the timing of complete destruction of the pathogen or the degree of its suppression when the final elimination of the pathogen from the body is carried out by immunological mechanisms (V.K. Tatochenko, 1994). Complete elimination of the pathogen in uncomplicated pneumonia can be achieved by 7-10 days of using antibacterial agents. Therefore, in the uncomplicated course of typical pneumonia, the duration of antibacterial therapy can be limited to 7-10 days. For pneumonia of chlamydial origin, antibacterial therapy with macrolides should be carried out for at least 14 days (Red Book, 1994). In this case, as a rule, complete elimination of the pathogen occurs. The exception is azithromycin, the duration of treatment of which is 3-5 days.

ANTIBACTERIAL DRUGS USED FOR THE TREATMENT OF RESPIRATORY INFECTIONS IN CHILDREN IN AN OUTPATIENT CONDITION

Penicillins

Natural penicillins for oral use

Natural penicillins for oral use remain the drugs of choice in the treatment of upper respiratory tract infections such as tonsillitis, pharyngitis, and exacerbation of chronic tonsillitis. The narrowing of the range of clinical use of natural penicillins is associated with the wide distribution of penicillin-resistant strains among the main pneumotropic pathogens.

Table 12.
Natural penicillins for oral use (phenoxymethylpenicillin preparations are registered and approved for use in the Russian Federation)*

Trade name of the drug	Release form
Phenoxymethyl penicillin	table 0.25 granules for preparing a suspension (in 5 ml of the finished suspension - 125 mg of phenoxymethylpenicillin)
Ospen	table 0.25 (0.5) granules for preparing a suspension (in 5 ml of the finished suspension - 400,000 units of phenoxymethylpenicillin) syrup (in 5 ml of syrup - 400,000 (700,000) units of phenoxymethylpenicillin)
V-penicillin	table 0.25 (440000 units) tab. 0.5 (880000 units)
Vepicombin	table 300,000 (500,000 and 1,000,000) IU suspension (in 5 ml of suspension - 150,000 IU of phenoxymethylpenicillin) drops for oral administration (in 1 ml of drops - 500,000 IU of phenoxymethylpenicillin)
Cliacyl	table 1 200000 ME powder for making syrup (5 ml syrup - 300000 IU phenoxymethylpenicillin)
Megacillin yelled	table 600,000 (1,000,000) ME granulate for preparing a suspension (in 5 ml of suspension - 300,000 IU of phenoxymethylpenicillin)

* - State Register of Medicines, 1996; Register of Medicines of Russia 97/98,1997; Vidal,1998

The active substance of natural penicillins for oral use is phenoxymethium penicillin. Table 12 presents phenoxymethylpenicillin preparations registered and approved for use in the Russian Federation.

Doses and route of administration of phenoxymethylpenicillin: Daily dose: children under 10 years old - 50-100 thousand units/kg, children over 10 years old - 3 million units per day.

1 mg of the drug corresponds to 1600 units of phenoxymethylpenicillin. The frequency of administration is 4-6 times a day, 1 hour before or 2 hours after meals. Course duration is 5-10 days.

Adverse reactions. When using phenoxymethylpenicillin, allergic reactions are possible (urticaria, erythema, Quincke's edema, rhinitis, conjunctivitis, etc.). Stomatitis and pharyngitis may occur as a manifestation of an irritant effect on the mucous membranes of the oropharynx.

Contraindications. Hypersensitivity to penicillins.

Broad-spectrum semi-synthetic penicillins, penicillinase-resistant (“protected” aminopenicillins)

Among semisynthetic penicillins, which have a wide spectrum of antibacterial action, aminopenicillins are more often used in pediatric practice for the treatment of bacterial infections of the respiratory tract. At the same time, domestic pediatricians most widely use ampicillin. However, there is a more active form of ampicillin - amoxicillin. Amoxicillin is an active metabolite of ampicillin and has the same spectrum of antibacterial action. At the same time, amoxicillin is 5-7 times more active than ampicillin. In addition, amoxicillin is much better absorbed from the gastrointestinal tract. The degree of absorption of amoxicillin from the gastrointestinal tract does not depend on the intake and composition of food. Amoxicillin also produces higher concentrations in sputum.

A significant disadvantage of aminopenicillins is their sensitivity to the effects of bacterial beta-lactamases. Considering the significant increase in beta-lactamase-producing strains among pneumotropic pathogens (Table 5), it is advisable to use aminopenicillins in combination with substances that have an inhibitory effect on bacterial beta-lactamases. The most often used as “protection” for semisynthetic penicillins are clavulanic acid and sulbactam. Clavulanic acid and sulbactam irreversibly inhibit plasmid-encoded beta-lactamase (penicillinase) and thereby significantly increase the antibacterial activity and spectrum of action of aminopenicillins combined with them. At the same time, it should be remembered that the probability of induction of the synthesis of chromosomal beta-lactamase in bacteria under the influence of clavulanic acid has been established.

Most often in pediatric practice, combinations of amoxicillin with clavulanic acid and ampicillin with sulbactam (sultamicillin) are used in the treatment of respiratory infections (Table 13 and Table 14).

When using amoxicillin preparations potentiated with clavulanic acid, the dose calculation is based on amoxicillin.

Doses and method of administration of the combination of Amoxicillin + clavulanic acid.

Table 13.
Drugs combining amoxicillin and clavulanic acid, registered and approved for use in the Russian Federation*

* - State Register of Medicines, 1996; Register of Medicines of Russia 97/98, 1997; Vidal, 1998.
** - the content of amoxicillin is presented in finished dosage forms.

Table 14.
Preparations of sultamicillin* (ampicillin + sulbactam), registered and approved for use in the Russian Federation**

* - Sultamicillin is a registered international name for the combination of active substances - double ester of ampicillin and sulbactam.
** - State Register of Medicines, 1996; Register of Medicines of Russia 97/98. 1997: Vidal. 1998.

Daily dose (calculation based on amoxicillin):

Children under 2 years of age - 20 mg/kg,
- children aged 2-5 years - 375 mg/day,
- children aged 5-10 years - 750 mg/day,
- children over 10 years old - 750 mg - 1 g / day. Frequency of reception - 3 days. Course - 5-14 days.

Adverse reactions. When using a combination of amoxicillin and clavulanic acid, allergic reactions may develop. Rarely: dyspeptic symptoms, liver dysfunction (hepatitis, cholestatic jaundice), pseudomembranous colitis.

Contraindications. Hypersensitivity to penicillins, cephalosporins, clavulanic acid. Infectious mononucleosis.

Doses and method of administration of sultamicillin(combination of ampicillin with sulbactam):

Treatment with sultamicillin for moderate and severe forms of respiratory infections caused by bacterial pathogens can be carried out using a “step-by-step” method. Initially, during the period of pronounced manifestations of infectious toxicosis, parenteral administration of the drug is prescribed, and when the condition improves, they switch to oral administration. Daily dose for parenteral administration: 150 mg/kg/day of sultamicillin (corresponding to 100 mg/kg/day of ampicillin). The frequency of intramuscular administration is 3-4 times a day. Daily dose for oral administration:

Children weighing less than 30 kg - 25-50 mg/kg/day of sultamicillin,
- children weighing more than 30 kg - 375-750 mg/day of sultamicillin." Frequency of administration - 2 times a day. Course - 5-14 days.

Adverse reactions. When using a combination of ampicillin and sulbactam, allergic reactions, diarrhea, nausea, vomiting, epigastric pain, intestinal colic, drowsiness, malaise, headache, and rarely, enterocolitis and pseudomembranous colitis are possible.

Contraindications. Hypersensitivity to the components of the drug, intolerance to penicillins, cephalosporins. Infectious mononucleosis.

2nd generation cephalosporins

In recent years, in the treatment of respiratory infections in children, the choice of antibiotics from the group of cephalosporins has been in favor of 2nd generation drugs. This is due to the low activity of 1st generation cephalosporins (cephalexin, cefadroxil, cefradine) against Haemophilus influenzae and moraxella, as well as due to their destruction under the influence of most beta-lactamases. Unlike 1st generation cephalosporins, 2nd generation cephalosporins are highly active against Haemophilus influenzae and Moraxella. In addition, 2nd generation cephalosporins are more resistant to the action of beta-lactamases.

Oral forms of 2nd generation cephalosporins are most often used in outpatient settings. However, for moderate and severe forms of bacterial respiratory infections, it is possible to carry out “stepped” therapy with appropriate 2nd generation cephalosporin drugs.

When treating bacterial respiratory infections with severe manifestations of intoxication and febrile fever, “stepped” antibacterial therapy using 2nd generation cephalosporins is advisable. In this case, the drug of choice for parenteral administration is cefuroxime (zinacesr): zinacef (cefuroxime for parenteral administration) at a dose of 60-100 mg/kg/day - 3 IM injections.

After the child’s condition improves and the symptoms of intoxication decrease and the temperature reaction normalizes, antibacterial therapy continues with the use of the oral form of cefuroxime axetil (Zinnat).

Adverse reactions. When using cefaclor, allergic reactions, diarrhea, nausea, vomiting, dizziness, and headache are possible. When using cefuroxime, similar adverse reactions are observed, with gastrointestinal disorders being more common. In rare cases, pseudomembranous colitis develops. With long-term use in high doses, changes in the peripheral blood picture (leukopenia, neutropenia, thrombocytopenia, hemolytic anemia) are possible.

Sulfonamide drugs

Sulfonamide drugs (sulfonamides) are a group of chemotherapeutic agents with a broad antimicrobial spectrum of action. Sulfonamides are derivatives of sulfanilic acid amide.

Sulfanilic acid amide was synthesized by P. Gelrno in 1908. However, only in the early 30s of the 20th century was the high antibacterial effectiveness of its derivatives established and widespread use in medical practice began (F. Mietzsch, J. Klarer, 1932; G. Domagk, 1934; J. TrefoueletaL, 1935).

The mechanism of the antimicrobial action of sulfonamides

For normal life activity and reproduction of microorganisms, a certain level of nucleotide biosynthesis, controlled by growth factors, is required. Bacteria are not able to use exogenous growth factors (folic and dihydrofolic acids), because their shell is impermeable to these compounds. To synthesize their own growth factors, bacteria capture from the outside the precursor of folic acid - para-aminobenzoic acid (PABA). The latter is structurally close to sulfonamide drugs. Because of this similarity, microbial cells “erroneously” capture sulfonamides instead of PABA. Sulfanilamide entering the bacteria competitively displaces PABA from the metabolic cycle and disrupts the formation of folic acid and its precursors. The latter leads to disruption of metabolic processes in the microbial cell and to the loss of its reproductive functions. Thus, sulfonamides have a bacteriostatic effect. The mechanism of the antimicrobial action of sulfonamide drugs is based on the blockade of folic acid synthesis in bacteria with subsequent disruption of the formation of nucleotides, suppression of the vital activity and reproduction of microorganisms.

Sulfonamides are rightfully considered the first modern chemotherapeutic antimicrobial agents. The use of sulfonamide drugs played a significant role in reducing the mortality and severity of various infectious diseases (R.J. Schnitzer, F. Hawking 1964). However, in recent decades, the indications for the use of sulfonamides in pediatric practice have sharply narrowed due to the widespread use of antibiotics. At the same time, the list of sulfonamide drugs recommended for use in children was significantly reduced (R.E. Behrman, 1983; G. Peter, 1991). Thus, in the treatment of infectious diseases of the respiratory system, of all sulfa drugs, the use of only biseptol is currently considered justified (Belousov Yu.B., Omelyanovsky V.V., 1996).

Biseptol (TMP/SM) is a combined broad-spectrum antimicrobial drug. The composition of biseptol includes: sulfonamide - sulfamethoxazole and a diaminopyrimidine derivative - trimethoprim.

The history of the creation of the drug is associated with attempts to achieve a bactericidal effect when using therapeutic doses of sulfonamides. It turned out that the combination of sulfamethoxazole with trimethoprim in usual dosages leads not only to an increase in the bacteriostatic effect by almost 100 times, but also to the appearance of a bactericidal effect (R.M. Bushby, 1967 "And Ganczarski, 1972).Further studies showed that maximum antibacterial and therapeutic effectiveness was observed with a combination of trimethoprim and sulfamethoxazole in a ratio of 1: 5. In this case, it was possible to achieve optimal synergy between the ingredients included in the drug.

Table 15.
2nd generation cephalosporins for oral use registered and approved for use in the Russian Federation*

* - State Register of Medicines, 1996.

The mechanism of antimicrobial action of biseptol

It turned out that the increase in antimicrobial activity and the development of a bactericidal effect when combining 2 bacteriostatic drugs (trimethoprim and sulfamethoxazole) is associated with a double blocking effect. Sulfamethoxazole, which is part of Biseptol, like all sulfonamides, competitively replaces PABA and prevents the formation of dihydrofolic acid. In turn, the second component of biseptol - trimethoprim - blocks the next stage of folic acid metabolism, disrupting the formation of tetrahydrofolic acid. Inhibition by biseptol of successive stages of the synthesis of growth factors in a microbial cell leads to pharmacological potentiation and the development of a bactericidal effect.

By blocking different stages of folic acid biosynthesis in the microbial cell, both components of the drug - trimethoprim and sulfamethoxazole - not only potentiate the bacteriostatic effects of each other, but lead to the appearance of the bactericidal effect of biseptol.

Antimicrobial spectrum of action of biseptol

Biseptol is a combined chemotherapeutic agent with a broad antimicrobial spectrum of action.

It should be noted that biseptol is active against many gram-positive and gram-negative microorganisms. Pathogens such as streptococci (including pneumococcus), Moracella, Haemophilus influenzae and staphylococci, which are the main etiological agents for bacterial respiratory infections, are highly sensitive to biseptol. Table 16 shows the antimicrobial spectrum of action of biseptol. Pseudomonas aeruginosa, treponema, mycoplasma, mycobacterium tuberculosis, viruses and fungi are resistant to Biseptol.

Biseptol is the drug of choice (“Drug of choice”) for pneumocystosis, nocardiosis, and coccidiosis. Biseptol is considered as an alternative first-line drug for intestinal scratch disease. Biseptol can also be used as an alternative or reserve drug for infectious diseases caused by streptococci, pneumococci, moraxella, Haemophilus influenzae, staphylococci, enterobacteria, toxoplasma (in combination with other chemotherapeutic drugs) and Brucella (in combination with rifampicin).

It should be noted that microorganisms may develop plasmid-associated resistance to Biseptol.

Pharmacokinetics of biseptol

After oral administration, Biseptol is quickly and well absorbed from the gastrointestinal tract. Bioavailability of the drug is 90-100%. The maximum concentration in blood plasma after oral administration is achieved within 2-4 hours, and a constant therapeutic concentration after a single dose is maintained for 6-12 hours (on average 7 hours). The components of biseptol (trimethoprim and sulfamethoxazole) bind to plasma proteins by 45% and 60%, respectively. Constant plasma concentrations of both components of Biseptol with a 2-fold daily dose are achieved within 3 days from the start of therapy. The half-life of Biseptol is 10-12 hours.

Sulfamethoxazole, which is part of Biseptol, is excreted from the body both in unchanged (active) form and in the form of hepato-biotransformation products. Sulfamethoxazole undergoes biotransformation in the liver by acetylation. Acetylated metabolites lose their antibacterial activity and are excreted from the body by glomerular filtration and are not capable of tubular reabsorption. Acetylated metabolites are poorly soluble in water, and in the acidic environment of the urine of the renal tubules they can even precipitate. In children, only 30-50% of the administered dose of sulfamethoxazole undergoes acetylation, while in adults it is 60-80%. It has been established that in children of the 1st year of life, the processes of acetylation of sulfamethoxazole are reduced and amount to 27%, and biotransformation also occurs due to glucuronidation. This creates the preconditions for increasing the concentration of active sulfamethoxazole not only in urine, but also in plasma, since its non-acetylated metabolites are able to be reabsorbed in the renal tubules. Consequently, in children of the first 12 months, the therapeutic effect of Biseptol can be achieved even with low doses. This is a fundamental position and must be taken into account when prescribing the drug to children 1 year of age. With age, the processes of hepatic acetylation of sulfamethoxazole are activated. Thus, in children aged 5 years, the amount of acetylated sulfamethoxazole is already 45%, and in children over 12 years old it approaches the values ​​of adults.

Table 16.
Antimicrobial spectrum of biseptol

Aerobic bacteria
cocci	sticks	cocci	Sticks
Staphylococcus spp. (including those producing penicillinase) Streptococcus spp. (including pneumococcus)	Corynebacterium diphteriae Nocardia asteroids Listeria monocytogenes	Neisseria Gonorrhoeae Moraxella catarrhalis	Escnerichia coli Shigella spp. Salmonella spp. Proteus spp. Enterobacter spp. Klebsiella spp. Yersinia spp. Vibriocholerae Haemophilus inf.
Anaerobic bacteria
Gram-positive microorganisms		Gram-negative microorganisms
cocci	sticks	cocci	Sticks
-	-	-	Bacteroides spp.
Protozoa
Toxoplasma gondii, Pneumocystis carinii, Isospora belli, Cyclospora

Trimethoprim is eliminated from the body through glomerular filtration. No more than 10-20% of the drug undergoes biotransformation, therefore 80-90% of trimethoprim is excreted in the urine in unchanged (active) form. In children of the first 3 months of life, the elimination of trimethoprim is reduced, because there is a functional immaturity of glomerular filtration - the main route of elimination of the drug from the body. This creates the preconditions for the occurrence of very high concentrations of trimethoprim in plasma. It should also be noted that although only 10-20% of trimethoprim is metabolized in the body, the resulting compounds (N-oxides) are highly histiotoxic.

Biseptol penetrates well into organs and tissues. When using conventional therapeutic doses of Biseptol, effective bactericidal concentrations of its components are achieved in blood plasma, lung tissue, sputum, cerebrospinal fluid of the inner ear, kidneys, and soft tissues. Biseptol penetrates the blood-brain barrier and also creates effective bactericidal concentrations in the cerebrospinal fluid.

Biseptol easily passes through the placental barrier. At the same time, plasma concentrations of the drug in the blood of the fetus may be close to those of a pregnant woman (V.A. Ritschel, 1987; R. Petel, P. Welling, 1980).

It should be remembered that the use of Biseptol by a lactating woman is accompanied by penetration of the drug into the mammary glands and its release into milk.

Side and undesirable effects when using Biseptol

The use of recommended doses and duration of therapy with Biseptol rarely leads to serious complications. In some cases, the use of Biseptol may be accompanied by the development of side effects. In young children, adverse events when using Biseptol may occur more often than in older age groups. This is due to the high and intense level of metabolic processes in children in the first years of life.

Table 17.
Daily therapeutic doses of Biseptol

The high need for folic acid in young children creates the preconditions for more frequent occurrence of undesirable effects when taking Biseptol. This is due to the fact that folic acid metabolism may be disrupted not only in bacteria, but also in the cells of the child’s body. The latter may be accompanied by clinical manifestations of vitamin B deficiency with the development of dyspeptic disorders and suppression of hematopoiesis (Table 17). It has been established that gastrointestinal dysfunctions occur in 9.2% of children who used Biseptol (C. Marchantetal., 1984; W. Feldman et al., 1990). Information on the incidence of platelet- and neutropenia (the vast majority of asymptomatic ones) is contradictory and, according to I.V. Markova and V.I. Kalinicheva (1987) from 16 to 50% of treated children. It was noted that attempts to use folic acid did not eliminate these side effects of biseptol (N.P. Shabalov, 1993). At the same time, the use of the active metabolite of folic acid - folinic acid (citrovorum factor) led to the relief of vitamin B deficiency. Currently, calcium folinate and leucovorin, the active principle of which is folinic acid, are registered and approved for use in the Russian Federation. In case of development of folic acid deficiency in the child's body, calcium folinate or leucovorin is prescribed, depending on age, 1-3 mg 1 time per 3 days per os, less often - parenterally.

Due to the biotransformation of sulfamethoxazole in the liver and subsequent elimination through the kidneys, crystals of its acetylated metabolites may form in the renal tubules. The latter disrupt the functioning of the tubular parts of the kidneys and, in severe cases, can lead to the development of interstitial nephritis. These side effects develop in cases where a rational drinking regime is not observed and medications that acidify urine (ascorbic acid, calcium chloride, methenamine) are simultaneously used. Drinking plenty of alkaline water prevents these complications. Therefore, during therapy with Biseptol, the amount of fluid consumed by the child must be monitored.

In newborns, premature and morpho-functionally immature children in the first weeks and months of life with conjugation jaundice, the use of biseptol can lead to the displacement of bilirubin from compounds with plasma proteins and cause bilirubin encephalopathy. In this regard, biseptol is contraindicated for children of the first year of life with indirect hyperbilirubinemia (N.P. Shabalov, 1993).

The use of Biseptol in children of the first year of life can also occasionally be accompanied by the development of metabolic acidosis and hypoxia. This is due to the ability of sulfamethoxazole, which is part of Biseptol, to convert fetal hemoglobin into methemoglobin. It is believed that the simultaneous administration of vitamins C, E and glucose will prevent this complication.

Among the side effects of biseptol, photosensitivity, hypersensitivity and liver damage are also described.

It should be remembered that in children with impaired activity of erythrocyte enzymes (usually glucose-6-dehydrogenase deficiency), the use of biseptol can provoke a hemolytic crisis.

Interaction of Biseptol with other drugs

Using V In practical work when treating children with combinations of various pharmacological agents, the doctor must necessarily take into account possible interactions of drugs in the patient’s body. The latter can lead to both potentiation and weakening of the expected therapeutic effects, as well as contribute to increased toxic manifestations (L. Boreus, 1982).

Thus, it has been established that the antimicrobial activity of biseptol decreases with the simultaneous administration of drugs containing derivatives of para-aminobenzoic acid (novocaine, anesthesin, almagel-A). As a result of the structural identity between sulfamethoxazole and para-aminobenzoic acid included in these preparations, the accumulation of one of the active components of biseptol in the microbial cell is reduced. The latter leads to a sharp decrease in the bactericidal activity of the drug.

The antimicrobial activity of biseptol may also be reduced when administered simultaneously with barbiturates. This is due to the activation by barbiturates of liver enzyme systems involved in the biotransformation of sulfamethoxazole. As a result, the amount of unchanged (active) sulfonamide component biseptol is significantly reduced.

As noted above, the combined use of biseptol with drugs such as ascorbic acid, calcium chloride and methenamine promotes pronounced acidification of urine and, consequently, increased crystallization of acetylated metabolites of sulfamethoxazole.

The simultaneous use of biseptol with non-steroidal anti-inflammatory drugs and isoniazid leads to an increase in plasma concentrations of unchanged, active components of the drug (trimethoprim and sulfamethoxazole) and may enhance their toxic effects.

It should be remembered that the combined use of biseptol with diuretics increases the risk of developing thrombocytopenia.

It should be noted that Biseptol, in turn, can also enhance the undesirable effects of a number of drugs. So, with the simultaneous use of biseptol with diphenin, the risk of developing the toxic effects of the latter (nystagmus, ataxia, mental disorders) increases. The combined use of biseptol with indirect anticoagulants (phenyline) can lead to the development of hemorrhagic syndrome. When prescribing Biseptol to patients receiving antidiabetic drugs (sulfaurea derivatives - butamide, etc.), one should remember the possible potentiation of the hypoglycemic effect.

Thus, the simultaneous use of Biseptol and thiazide diuretics, oral antidiabetic agents, para-aminobenzoic acid derivatives, indirect anticoagulants, nonsteroidal anti-inflammatory drugs, and barbiturates is not recommended.

Dosage regimen and method of use of biseptol

Biseptol is not prescribed to premature babies, newborns and children under 3 months due to the risk of developing kernicterus.

Biseptol is administered orally 2 times a day (morning and evening) with an interval of 12 hours.

In patients with impaired renal function, in which endogenous creatinine clearance decreases to 30 ml/min and below, half the age-specific doses (1/2 the age-specific therapeutic dose) should be used.

The duration of biseptol therapy for acute infections is 5-7 days.

When using Biseptol, be sure to follow a rational drinking regimen. To do this, the volume of liquid consumed by the child must be monitored daily.

Macrolides

The uncontrolled use of macrolides in the form of routine therapy for various clinical variants of respiratory infections, including viral etiology (!), has led to the emergence of resistant strains of microorganisms. It has been established that penicillin-resistant pneumococcal strains in almost half of the cases (41%) are resistant to 14-member (erythromycin, roxithromycin, clarithromycin) and 15-member (azithromycin) macrolides (J. Hofman et al, 1995 ). At the same time, penicillin- and erythromycin-induced resistant pneumococci and pyogenic streptococci remain sensitive to 16-member macrolides (spiramycin, zosamycin) (K. Klugman, 1996).

In addition to the antibacterial effect, macrolides, by inhibiting the oxidative burst and influencing the production of cytokines, have an anti-inflammatory effect (C. Agen et al., 1993; A. Bryskier et al., 1995). The stimulating effect of macrolides on neutrophil phagocytosis and killing has been established (M.T. Labro et al., 1986; W. Horn et al., 1989). Macrolide antibiotics are also characterized by a pronounced anti-antibiotic effect (I. Odenholt-Toinqvist et al., 1995).

The appearance on the domestic pharmaceutical market of macrolides, which have better tolerability compared to erythromycin, allows their widespread use even in infants. The pharmacokinetic features of the “new” macrolides increase the compliance of the course (L.S. Strachunsky, S.N. Kozlov, 1998).

Table 18 presents the international names and trade names, doses and routes of administration of macrolides most commonly used in pediatrics.

When choosing a drug from the group of macrolides, especially in young children, preference is given to semi-synthetic 14-member (roxithromycin, clarithromycin, etc.), 15-member (azithromycin) and 16-member (midecamycin acetate, etc.). This is due to the fact that when using “new” macrolides, unwanted and side effects develop much less frequently. Most rarely, gastrointestinal disorders are observed with the use of 16-member macrolides (midecamycin acetate, etc.). This is related to that. that they, unlike other macrolides, do not have a motilinomimetic effect and do not cause hypermotility in the digestive tract (P. Peritietal., 1993). The nature of the interaction with drugs taken by the child simultaneously with macrolides must be taken into account (Table 19).

Table 18.
Macrolide antibiotics for oral use, registered and approved for use in the Russian Federation*

International and trade names	Release form, dose and method of administration
Erythromycin grunamycin, ilozon, ermiced, eric, erigexal, erythromycin, etomite)	table and capo. 0.1 (0.2; 0.25; 0.5), granulate for the preparation of suspension (in 5 ml of suspension - 0.125 (0.2; 1.83) erythromycin) suspension and syrup (in 5 ml - 0.1 25 (0.25) erythromycin), rectal suppositories (1 stick - 0.05 (0.1)) g erythromycin). Daily dose: 30-50 mg/kg. Frequency of intake - 4 days, between meals. Course - 5-14 days.
Clarithromycin (clacid, fromilid)	table 0.25 (0.5), dry solution for preparing a suspension (in 5 ml of suspension - 125 mg of clarithromycin). Daily dose: 7.5 mg/kg/day. Frequency of reception - 2 days. Course - 7-10 days.
^oxythromycin renicin, roxibid, eoximizan, rulide)	table 0.05 (0.1; 0.15; 0.3). Daily dose: 5-8 mg/kg/day. The frequency of administration is 2 times a day, before meals. Course - 7-10 days.
Azithromycin Azivok, Sumamed)	table and cape. 0.125 (0.25; 0.5), syrup (in 5 ml of syrup - 100 (200) mg of azithromycin). Daily dose (for children with BW>10 kg): Course - 5 days: or Course - 3 days: on day 1 - 10 mg/kg, on days 2-5 - 5 mg/kg, on days 2-3 - 10 mg /kg. Frequency of reception - 1 day.
Midecamycin (macropen)	table 0.4, dry solution for preparing a suspension (in 5 ml of suspension - 1 75 mg of midecamycin acetate). Daily dose: 30-50 mg/kg/day. Frequency of reception - 2 days. Course - 5-14 days.
Spiramycin (Rovamycin)	table 1.5 (3.0) million ME sachets with granulate for preparing a suspension (in 1 sachet - 0.375 (0.75; 1.5) million MEspiramycin). Daily dose: 1.5 million IU/10kg/day. Frequency of reception - 2-4 days. Course 5-14 days.
Josamycin (vilprafen)	table 0.5 suspension (in 5 ml of suspension - 150 (300) mg of josamycin). Daily dose: 30-50 mg/kg/day. Frequency of intake - 3 days, between meals. Course - 7-10 days.

* - State Register of Medicines, 1996: Register of Medicines of Russia 97/98, 1997; Vidal, 1998.

Table 19.
Drug interactions of macrolides (according to D.S. Strachunsky and S.N. Kozlov (1996), modified and supplemented)

Macrolides	Drugs	Result of interaction
Erythromycin Clarithromycin Midecamycin	Indirect anticoagulants (warfarin, etc.)	Increased hypoprothrombin
Erythromycin Clarithromycin Midecamycin Josamycin	Carbamezepine (t egr eto l, fi n l e p s i n	Increased toxicity of carbamezepine due to increased serum concentrations
Erythromycin Klar ig om icin Ro xitr om icin	Cardiac glyxides (digocoin)	Increased digoxin toxicity due to increased serum concentrations
Erythromycin Clarithromycin Josamycin	Other antihistams (terfenadine, astemizole)
Erythromycin Kl ar game om icin Ro xitr om icin Josamycin	Theophylline	Increased theophylline toxicity due to increased serum concentrations
Erythromycin Roxithromycin	Benzodiazepines (triazolam, mi do zolam)	Increased sedative effect of benzodiazepines
Erythromycin	Valproic acid (Depakine, Convulex)	Increased sedative effect of valproate
Erythromycin	Methylprednisolone	Prolongation of the effect of methyl-prednisolone
Erythromycin Clarithromycin	Cisapride (coordinax, peristil)	High risk of developing ventricular arrhythmias
Erythromycin Kl ar games om its in	Dizopyramid (rhythm ilen, rigmodan)	Increased risk of disopyramide toxicity

Midecamycin does not affect the pharmacokinetics of theophylline.

Antacids, when used simultaneously with azithromycin, reduce its absorption from the gastrointestinal tract.

It should be noted that the simultaneous use of macrolides with ergot alkaloids or ergotamine-like vasoconstrictors promotes the development of ergotism with the development of a pronounced vasoconstrictor effect (up to the development of tissue necrosis of the extremities).

Adverse reactions. Macrolides are reliably considered one of the safest antibiotics. When using macrolides, serious adverse reactions are extremely rare. Among the undesirable manifestations, nausea, vomiting, abdominal pain are most often observed, and less often - diarrhea. With long-term use of “old” macrolides, the development of cholestatic hepatitis is possible.

Contraindications. Severe liver dysfunction. Increased individual sensitivity to macrolides. The simultaneous use of macrolides and ergot alkaloids, as well as ergotamine-like vasoconstrictors, is undesirable.

CONCLUSION

The problem of respiratory infections in children, despite significant progress in medical science in recent decades, continues to remain relevant.

The significant incidence of bacterial respiratory infections, as well as the high incidence of serious bacterial complications against the background of ARVI, require timely and justified inclusion of antibacterial drugs in therapy. However, despite the huge arsenal of highly active antibacterial agents, treatment of respiratory infections is not always successful. Late prescription, as well as a formulaic approach to the selection of antibacterial drugs, leads to an increase in the resistance of pneumotropic pathogens, which often causes the ineffectiveness of the etiotropic therapy. At the same time, a targeted and timely choice of initial etiotropic treatment, based on an empirical determination of the probable causative agent of a respiratory infectious disease, allows in practice, even without the possibility of bacteriological identification of the etiological factor, to achieve a clinical effect and a positive result of therapy in general.

The timeliness of prescription and the correct choice of antibacterial therapy, and therefore the effectiveness of treatment in general, are possible only if a number of factors are analyzed. The nosological form of the respiratory infection must be taken into account, since there is a certain connection between specific pneumotropic pathogens and the localization of damage to the respiratory tract. Based on epidemiological data, conclusions are drawn about the degree of sensitivity of probable pathogens to antimicrobial agents. Also, the choice of antibacterial drugs should be based on an analysis of the pharmacokinetic characteristics of the drug. This will determine the possibility of achieving an effective therapeutic concentration of the drug in damaged tissues and the likelihood of the risk of developing its side and undesirable effects. A rational choice of antibacterial therapy is possible only with mandatory consideration of the child’s age, his individual characteristics and background conditions.

Thus, the effectiveness of initial antibiotic therapy largely depends on the doctor taking into account the individual characteristics of the child, his age, the epidemiological situation and the nature of the infectious disease. Taking into account information about potential pathogens that most often cause infectious processes of a certain localization, as well as their sensitivity to antibacterial drugs, will make it possible to purposefully narrow the range of selected drugs. All this will make it possible to carry out rational etiotropic therapy in the early stages of the disease, reduce the risk of developing serious complications and increase the success of treatment of respiratory infections in general.

Infections are one of the main problems of the ICU (they can be the main reason for hospitalization of patients in the ICU or a complication of other diseases), the most important criterion for prognosis for patients. Community-acquired infections requiring hospitalization in the ICU and hospital-acquired infections are independent factors of mortality. They lead to longer hospital stays. Based on the above, to improve the prognosis of patients, it is fundamentally important to develop an antibacterial therapy strategy.

The difficulty of treating bacterial infections in the ICU is due to many factors, but the most important are:

• high level of resistance of pathogens to traditional antibiotics and rapid development of resistance during treatment,
• usually polymicrobial nature of the disease,
• severity of the patient's condition,
• frequent isolation of so-called problem microorganisms,
• frequent relapses or superinfection during and after the end of antibiotic therapy

In addition, the unjustified, unsystematic use of antibiotics leads to the rapid selection and spread of resistant strains of microorganisms.

Factors contributing to the development of infection in patients in the ICU:

• Main disease.
• The severity of the patient’s condition according to the APACHE II scale for assessing acute and chronic functional changes is >15.
• Age over 60 years.
• Diagnostic and therapeutic invasive procedures:
  • intubation,
  • bladder catheterization,
  • catheterization of central veins.
• Use of antacids and H2 receptor blockers.
• Length of stay in the ICU.

Unsystematic or widespread prophylactic use of antibiotics. The source of infection can be endogenous (oropharyngeal colonization or aspiration) or exogenous (respiratory equipment, catheters, medical personnel, other patients).

Due to the severity of the condition of patients and the danger of infectious complications for them, antibacterial therapy should be started urgently at the first signs of the disease (without waiting for the results of a bacteriological study), since delay can have dangerous consequences. In their daily hospital practice, doctors encounter two groups of infectious diseases:

• community-acquired - those that occurred outside the hospital and caused hospitalization,
• hospital (nosocomial) - developed in a patient in a hospital.

The main differences between these groups are the types of pathogens and their antibiotic resistance. Community-acquired infections are characterized by a limited and fairly stable composition of the most likely pathogens, depending on the localization of the process. The spectrum of pathogens causing nosocomial infections is generally less predictable. Pathogens of hospital-acquired infections are more resistant to anibiotics than pathogens of community-acquired infections. These differences are important for choosing rational empirical therapy.

In hospitals, and especially in intensive care units, favorable conditions have been created for the exchange of microorganisms and close contact between patients and staff. In parallel, against the background of intensive treatment, their selection occurs. As a result, a microecological situation arises with the dominance of certain strains (mostly resistant to antibiotics). They are called hospital ones. There are no clear criteria for recognizing a particular strain as hospital-acquired (antibiotic resistance is important, but not required).

Upon admission to the hospital, the patient inevitably comes into contact with hospital strains of bacteria. As the length of stay in a medical institution lengthens, the likelihood of replacing the patient's own microflora with hospital microflora increases - the risk of developing infections caused by it increases. It is quite difficult to accurately determine the period required for colonization of the patient’s body with hospital microflora, since it depends on many factors (age, stay in intensive care units, severity of concomitant pathology, antibiotic therapy or prophylaxis). It is also difficult to establish the time interval when an emerging infection should be considered hospital-acquired. In most cases, the infection is regarded as hospital-acquired when its symptoms appear more than 48 hours after hospitalization.

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Epidemiology and causes of infections

It is difficult to assess the frequency of hospital infections in our country due to the lack of official registration of such diseases. In the ICU, the risk of developing infectious complications in patients is 5-10 times higher than in general departments. A quarter of the total number of hospital infections occurs in intensive care units. According to international multicenter studies, the average prevalence of nosocomial infections in medical institutions is 5-10%, and in ICUs it reaches 25-49%. Scientific works devoted to the study of their etiology reflect the situation in the surveyed hospitals, therefore their results are extrapolated to other institutions with a large degree of convention. Even multicenter studies are not considered comprehensive, although they are the most representative.

The structure and etiology of infections in the ICU have been most fully studied. According to the multicenter EPIC study, conducted on one day in 1417 departments in 17 European countries (covering more than 10 thousand patients), 44.8% were diagnosed with infections, with the incidence of ICU-associated infections being 20.6%. The most common infections in the ICU were pneumonia (46.9%), lower respiratory (17.8%) and urinary tract infections (17.6%), angiogenic (12%). Gram-negative bacteria of the Enterobacteriaceae family dominated in the etiological structure (34.4% ), Staphylococcus aureus (30.1%), Pseudomonas aeruginosa (28.7%), coagulase-negative staphylococci (19.1%), fungi (17.1%). Many etiologically significant microorganisms showed resistance to traditional antibiotics, in particular, the prevalence of methicillin-resistant staphylococci was 60%, and in 46% P aeruginosa was resistant to gentamicin.

Similar results on the etiological structure of infections were obtained in another study. Its results also confirmed that the majority of patients in the ICU (72.9%) were prescribed antibiotics for therapeutic or prophylactic purposes. Moreover, the most common are aminoglycosides (37.2%), carbapenems (31.4%), glycopeptides (23.3%), and cephalosporins (18.0%). The list of drugs indirectly confirms the high level of antibiotic resistance of pathogens in the ICU. An analysis of the results of the US hospital infection control system for 1992-1997 showed the prevalence of urinary tract infections (31%), pneumonia (27%), and primary angiogenic infections (19%) in ICUs. Moreover, 87% of primary angiogenic infections were associated with central venous catheters, 86% of pneumonias were associated with mechanical ventilation, and 95% of urinary infections were associated with urinary catheters. The leading causative agents of pneumonia associated with mechanical ventilation (NPIV) were Enterobacteriaceae (64%), P. aeruginosa (21%), S. aureus (20%), among the causative agents of angiogenic infections were coagulase-negative staphylococci (36%), enterococci (16% ), S. aureus (13%), fungi (12%) Fungi and Enterobacteriaceae predominated in urinary infections.

Based on the primary localization of the source of infection, one can judge the presumed etiology of the disease, which, of course, serves as a reliable guide to the choice of an empirical regimen of antibacterial therapy.

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Principles for planning antibacterial therapy for infections

Taking into account the indicated difficulties in the treatment of hospital infections (the severity of the patient’s condition, often their polymicrobial nature, the possibility of isolating pathogens with multiple resistance to antibacterial agents during nosocomial infections), it is necessary to highlight the following principles for the rational use of antibiotics in the ICU:

• Antibacterial therapy begins immediately after detection of infection, without waiting for the results of bacteriological examination.
• The choice of the starting empirical treatment regimen should be programmable, taking into account the likely spectrum of pathogens and their possible resistance (data from local monitoring of antibiotic resistance).
• The initial assessment of the effectiveness of therapy is carried out 48-72 hours after its start, reducing the severity of fever and intoxication. If there is no positive effect within the specified time frame, the therapy regimen is adjusted.
• It is irrational and undesirable to use prophylactic antibiotics in the postoperative period or during mechanical ventilation (in the absence of clinical signs of infection).
• Antibiotics are administered in accordance with official instructions. The main routes of administration are intravenous, intramuscular, and oral. Other routes (intraarterial, endolymphatic, intra-abdominal, endotracheal, etc.) have no proven advantages over traditional ones.

The choice of antibacterial drug can be made based on the established etiology of the disease and the specified sensitivity of the pathogen to antibiotics - etiotropic therapy. In situations where the causative agent is unknown, the drug is prescribed based on an empirical approach. In the latter case, the antibiotic is chosen based on the known list of microorganisms that cause infection in a certain localization, and knowledge of the main trends in antibiotic resistance of the most likely pathogens. It is clear that in clinical practice, most often, before clarifying the etiology of the disease, the doctor is forced to use an empirical approach.

For severe infections, one should adhere to the principle of maximum initial empirical therapy - the prescription of drugs that act on the maximum number of potential pathogens of a given localization. Adhering to this principle is especially necessary when treating NSAIDs, peritonitis, and severe sepsis. Since it has been established that in the case of inadequate initial therapy, the risk of death significantly increases (for example, for NSPI - 3 times).

Adequate empirical antibacterial therapy means:

• with the selected mode, all potential pathogens are affected,
• when choosing an antibacterial drug, the risk of multidrug resistance of pathogens is taken into account,
• The treatment regimen should not contribute to the selection of resistant strains in the department.

Empirical and targeted etiotropic antibacterial therapy

Carrying out rational antibacterial therapy for hospital infections in the ICU is impossible without modern knowledge about the etiological structure of diseases and the antibiotic resistance of their pathogens. In practice, this means the need to identify the pathogen using microbiological methods and determine its antibiotic sensitivity. The choice of the optimal antibacterial drug can be discussed only after the above studies have been carried out.

However, in practical medicine the situation is not so simple, and even the most modern microbiological techniques are often unable to give the doctor a quick answer or even generally clarify the causative agent of the disease. In such a case, knowledge about the most likely causative agents of specific forms of hospital infections, the spectrum of natural activity of antibiotics and the level of acquired resistance to them in a given region and a particular hospital comes to the rescue. The last condition is most important when planning antibacterial therapy for hospital infections in the ICU, where the level of acquired resistance is highest. Since the insufficient equipment of microbiological laboratories and the low level of standardization of studies to assess antibiotic sensitivity do not allow us to form a real understanding of the epidemiological situation in a medical institution and develop balanced recommendations for treatment.

The etiology of infectious diseases is the main factor determining the strategy and tactics of antibacterial therapy. Due to the impossibility of rapid diagnosis of bacterial infections and assessment of the antibiotic sensitivity of their pathogens, the prescription of antibacterial therapy in intensive care usually occurs empirically.

Despite the significant diversity of infectious agents in intensive care, only a limited number of bacterial species play a leading role in their etiology. Based on the commonality of the spectra of natural sensitivity to antibacterial drugs and mechanisms of resistance, they can be combined into four groups:

1. S. aureus and a taxonomically heterogeneous subgroup of coagulase-negative staphylococci,
2. Enterococcus spp. (mainly E. faecalis),
3. representatives of the family Enterobacteriaceae,
4. Pseudomonas aeruginosa.

The listed pathogens are the sources of more than 80% of cases of urinary and respiratory tract infections, intra-abdominal and surgical site infections, as well as angiogenic infections. Infections of different localizations are characterized by certain etiological features. For example, angiogenic infections are most often caused by staphylococci, and urinary tract infections are caused by gram-negative microorganisms; enterococci practically do not affect the respiratory tract. Intra-abdominal and wound infections are characterized by the greatest etiological diversity.

The data presented can serve as a first guideline for choosing empirical antibacterial therapy. Microscopy of a smear from the source of infection is a very simple and, in some cases, extremely useful examination. Unfortunately, very little attention is paid to such a simple method in most institutions, despite the fact that information about the prevalence of gram-positive or gram-negative flora is extremely important for choosing antibacterial therapy.

Even more important information can be obtained a day after taking the pathological material and its initial culture. With a well-established laboratory and its connection with the clinic, the doctor can get an answer to the question “Are staphylococci, enterococci, enterobacteria or P. aeruginosa involved in the infectious process?” Knowing the spectrum of natural sensitivity of the listed groups of microorganisms and the characteristics of the spread of resistance in a particular institution, it is possible to adjust antibacterial therapy and, with a high degree of probability, ensure its adequacy.

The most accurate adjustment of antibacterial therapy is possible after obtaining the final results of identifying the pathogen and assessing its antibiotic sensitivity.

Below are data on the natural sensitivity spectrum of the main groups of infectious agents in the ICU and on the drugs of choice for the treatment of diseases of known etiology.

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Choice of antibiotic in the treatment of infections of known etiology

The section focuses on the drugs of choice for the treatment of severe and hospital-acquired infections. Other antibacterial drugs can be used to treat community-acquired and mild forms.

Streptococcus pyogenes

The drug of choice is benzylpenicillin. Aminopenicillins are equally effective; other ß-lactams do not offer benefits. Acquired resistance to ß-lactams has not been described.

Alternative drugs macrolides and lincosamides (indicated for allergies to ß-lactams).

The prevalence of acquired resistance varies among different geographic regions.

Streptococcus pneumoniae

The drugs of choice are benzylpenicillin (parenteral), amoxicillin (per os) and other ß-lactams.

The prevalence of acquired resistance varies among different geographic regions. For pneumonia caused by penicillin-resistant pneumococci, benzylpenicillin and amoxicillin are effective; for meningitis, failure is possible.

Alternative drugs - cephalosporins of the III-IV generations (cefotaxime, ceftriaxone, cefepime), carbapenems (for meningitis - meropenem), antipneumococcal fluoroquinolones. For meningitis caused by penicillin-resistant pneumococci, the use of glycopeptides is possible

Streptococcus agalactiae

It is advisable to combine the drugs of choice benzylpenicillin, ampicillin with aminoglycosides (gentamicin). Acquired resistance is a rare phenomenon.

Alternative drugs: III generation cephalosporins, carbapenems.

Viridans streptococci

The drugs of choice are benzylpenicillin, ampicillin. For endocarditis and severe generalized infections - in combination with aminoglycosides (gentamicin). Acquired resistance is a rare phenomenon.

Alternative drugs: III generation cephalosporins, carbapenems. For allergies to ß-lactams, glycopeptides can be used.

Enterococcus faecalis

The drugs of choice are benzylpenicillin or ampicillin in combination with gentamicin or streptomycin - endocarditis and severe generalized infections, ampicillin, nitrofurans or fluoroquinolones - urinary tract infections.

Acquired resistance occurs to penicillins, often to aminoglycosides.

Alternative drugs: glycopeptides (it is advisable to combine with aminoglycosides), oxazolidinones.

Acquired resistance to glycopeptides among the strains described in Russia is rare.

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Enterococcus faecium

The drugs of choice are glycopeptides (preferably in combination with aminoglycosides). However, treatment failures are possible.

Acquired resistance to glycopeptides among the strains described in Russia is rare.

Alternative drugs oxazolidinones

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Methicillin-sensitive staphylococci

The drugs of choice are oxacillin, protected aminopenicillins, and first generation cephalosporins.

Acquired resistance with sensitivity to oxacillin and simultaneous resistance to the ß-lactams listed above are unknown.

Alternative drugs: fluoroquinolones with increased activity against gram-positive microorganisms (levofloxacin, moxifloxacin, gatifloxacin), oxazolidinones. For severe infections and immediate allergies to ß-lactams, glycopeptides can be used, but their effectiveness is lower.

Methicillin-resistant staphylococci

The drugs of choice are glycopeptides. Acquired resistance: single resistant strains have been identified.

Alternative drugs oxazolidinones. Fluoroquinolones, fusidic acid, rifampicin, co-trimoxazole, and fosfomycin are sometimes effective. However, treatment regimens have not been precisely defined.

Corynebacterium diphtheriae

The drugs of choice are macrolides and lincosamides. The prevalence of acquired resistance has not been sufficiently studied.

Alternative drugs benzylpenicillin, rifampicin, tetracyclines.

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Corynebacterium jeikeium

The drugs of choice are glycopeptides. The prevalence of acquired resistance has not been sufficiently studied.

Alternative drugs have not been identified.

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Listeria monocytogenes

The drugs of choice are ampicillin, preferably in combination with gentamicin. Cephalosporins are ineffective. The prevalence of acquired resistance has not been sufficiently studied.

An alternative drug is co-trimoxazole. The clinical significance of in vitro sensitivity to macrolides, tetracyclines and chloramphenicol has not been determined.

Bacillus anthracis

The drugs of choice are benzylpenicillin, ampicillin. Cephalosporins are not very effective.

Alternative drugs: fluoroquinolones, tetracyclines, macrolides, chloramphenicol.

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Bacillus cereus

The drugs of choice are clindamycin, vancomycin. Acquired resistance has not been sufficiently studied. Alternative drugs gentamicin, ciprofloxacin.

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Nocardia asteroides

The drug of choice is co-trimoxazole. Acquired resistance has not been sufficiently studied.

Alternative drugs imipenem + glycopeptides, amikacin + cephalosporins, minocycline (their use is not sufficiently justified).

Neisseria meningitidis

The drug of choice is benzylpenicillin. Acquired resistance There have been isolated reports of the discovery of resistant strains.

Alternative drugs: III generation cephalosporins, chloramphenicol.

Haemophilus spp.

The drugs of choice are aminopenicillins. Acquired resistance In some regions, resistant strains producing β-lactamases are common (their share in Russia is less than 5-6%).

Alternative drugs: III generation cephalosporins, chloramphenicol. For localized infections - II generation cephalosporins, protected penicillins, fluoroquinolones.

Legionella spp.

The drugs of choice are erythromycin, azithromycin or clarithromycin (preferably in combination with rifampicin). There is no acquired resistance. Alternative drugs fluoroquinolones, doxycycline, co-trimoxazole.

Vibrio cholerae

The drugs of choice are fluoroquinolones. Acquired resistance has been described in isolated cases.

Alternative drugs doxycycline, co-trimoxazole.

Enterobacteriaceae

The drugs of choice for the treatment of severe infections caused by microorganisms of the Enterobacteriaceae family are β-lactam antibiotics. However, depending on the natural sensitivity of individual species, different drugs must be used. The use of aminoglycosides and fluoroquinolones is also justified. The choice of specific drugs is based on data on the location and severity of the infection and the spread of resistance.

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Escherichia coli, Proteus mirabilis

The drugs of choice are protected aminopenicillins, II-III generation cephalosporins. Acquired resistance is widespread.

Alternative drugs - fluoroquinolones, aminoglycosides, IV generation cephalosporins, cefoperazone + sulbactam, carbapenems (various combinations thereof). Resistance to all alternative drugs is possible. However, the least likely is to amikacin, carbapenems (resistance to them is an extremely rare phenomenon).

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Klebsiella spp, Proteus vulgaris, Citrobacter diversus

The drugs of choice are protected aminopenicillins, II-III generation cephalosporins. Acquired resistance is widespread.

Resistance to all alternative drugs is possible. However, the least likely is to amikacin, carbapenems (resistance to them is an extremely rare phenomenon).

Enterobacter spp, Citrobacter freundii, Serratia spp, Morganella morganii, Providencia stuartii, Providencia rettgeri

The drugs of choice are III-IV generation cephalosporins. Acquired resistance is widespread.

Alternative drugs: fluoroquinolones, aminoglycosides, cefoperazone + sulbactam, IV generation cephalosporins, carbapenems (various combinations thereof).

Resistance to all alternative drugs is possible. However, the least likely is to amikacin, carbapenems (there are isolated reports of resistant strains).

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Shigella spp.

The drugs of choice are fluoroquinolones. Acquired resistance is isolated cases.

Alternative drugs co-trimoxazole, ampicillin Salmonella spp., including S. typhi (generalized infections).

The drugs of choice are fluoroquinolones, third generation cephalosporins (cefotaxime, ceftriaxone). Acquired resistance is isolated cases.

Alternative drugs: chloramphenicol, co-trimoxazole, ampicillin.

Pseudomonas aeruginosa

Drugs of choice: ceftazidime + aminoglycosides. Acquired resistance is widespread.

Alternative drugs: protected antipseudomonal penicillins (used only in combination with aminoglycosides), ciprofloxacin, IV generation cephalosporins, carbapenems, polymyxin B.

It is possible to develop resistance to all alternative drugs.

Burkholderia cepacia

The drugs of choice are carbapenems, ciprofloxacin, ceftazidime and cefoperazone, ureidopenicillins (including protected ones), co-trimoxazole and chloramphenicol. However, treatment regimens are not well substantiated.

Acquired resistance is a fairly common occurrence. In cystic fibrosis, strains resistant to all of these drugs are especially common.

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Stenotrophomonas maltophilia

The drug of choice is co-trimoxazole. Acquired resistance is a relatively rare phenomenon.

Alternative drugs ticarcillin + clavulanic acid, doxycycline and minocycline, chloramphenicol. They may have sufficient activity, but the modes of their use are not sufficiently substantiated.

Strains that are resistant to alternative drugs are quite common.

Acinetobacter spp.

Drugs of choice due to the extreme diversity of strain sensitivity, it is difficult to justify empirical treatment regimens. The most commonly proposed combinations are carbapenems or ceftazidime with aminoglycosides (mainly amikacin), as well as fluoroquinolones with aminoglycosides. Prescribing ampicillin or cefoperazone with sulbactam may be effective (due to the latter's own antibacterial activity).

Acquired resistance to all drugs used is widespread.

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Clostridium petfringens

The drugs of choice are benzylpenicillin, possibly in combination with clindamycin. Acquired resistance has not been sufficiently studied.

Alternative drugs are almost all ß-lactams, chloramphenicol, metronidazole.

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Clostridium difficile

The drug of choice is metronidazole. Acquired resistance has not been described. An alternative drug is vancomycin.

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Actinomyces israelii and other anaerobic actinomycetes

The drugs of choice are benzylpenicillin and aminopenicillins. Acquired resistance has not been described. Alternative drugs: III generation cephalosporins, erythromycin and clindamycin, doxycycline.

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Peptostreptococcus

The drug of choice is benzylpenicillin. Acquired resistance is not widespread.

Alternative drugs are other ß-lactams, metronidazole, clindamycin, erythromycin, doxycycline.

Bacteroidesfragilis

The drug of choice is metronidazole. Acquired resistance is an extremely rare phenomenon.

Alternative drugs clindamycin, carbapenems, cefoxitin, protected penicillins.

Staphylococcus spp.

Currently, 34 species of staphylococci have been described. They are capable of producing a significant amount of various virulence factors. The most complete “set” of them is found in S. aureus strains. Isolation of bacteria from pathological material (with an appropriate clinical picture) almost always indicates their etiological significance.

In practice, precise species identification of staphylococci of other species, grouped into the “coagulase-negative” group, is often not necessary. Such information is important for epidemiological monitoring, as well as in the case of severe infections. Isolation of coagulase-negative staphylococci from non-sterile areas of the human body usually indicates colonization or contamination with pathological material. The problem of eliminating contamination arises even when such microorganisms are isolated from sterile environments (blood, cerebrospinal fluid).

Spectrum of natural sensitivity of Staphylococcus spp. and acquired resistance. Staphylococci are characterized by a high level of natural sensitivity to the vast majority of antibacterial drugs (beta-lactams, aminoglycosides, fluoroquinolones, macrolides, lincosamides, tetracyclines, glycopeptides, co-trimoxazole, chloramphenicol, fusidic acid and rifampicin). However, even with such great opportunities for choosing antibiotics, in some cases the treatment of staphylococcal infections is a serious problem, which is associated with the development of antibiotic resistance in microorganisms.

β-Lactam antibiotics

Among all antibacterial drugs, they are the most active against staphylococci, but due to the widespread distribution among bacteria, the ability to produce β-lactamases, natural and semi-synthetic penicillins have completely lost their clinical significance. Despite some differences in the level of microbiological activity, oxacillin, protected penicillins, cephalosporins of I-IV generations (except for ceftazidime and cefoperazone) and carbapenems have almost the same effectiveness. The choice of a specific drug depends on ease of use, cost and the likelihood of a mixed infectious process (involvement of gram-negative bacteria).

However, the use of β-lactam antibiotics is possible only in the absence of another resistance mechanism in staphylococci - an additional penicillin-binding protein. A marker of such a mechanism is resistance to oxacillin. According to historical tradition, S. aureus with a similar mechanism of resistance retained the name methicillin-resistant (Methicillin Resistant Staphylococcus aureus - MRSA), despite the fact that methicillin has long been practically excluded from medical practice.

If resistance to oxacillin is detected, treatment of staphylococcal infections with β-lactams is stopped.

The exception is the cephalosporin antibiotic ceftobiprole. It is able to suppress the activity of penicillin-binding protein of staphylococci.

An important feature of MRSA is the high frequency of associated resistance to antibacterial drugs of other groups (macrolides and lincosamides, aminoglycosides, tetracyclines and fluoroquinolones).

For a long time, MRSA was considered as exclusively hospital pathogens (their prevalence in many ICUs in Russia is more than 60%). However, recently the situation has changed for the worse; microorganisms are increasingly causing severe community-acquired infections of the skin and soft tissues, as well as destructive pneumonia.

Glycopeptide antibiotics (vancomycin, teicoplanin and a number of other drugs at various stages of development) are considered as the treatment of choice for the treatment of infections caused by MRSA. However, currently available glycopeptides (vancomycin and teicoplanin) exhibit only a bacteriostatic effect against staphylococci (a significant disadvantage compared to β-lactams). In cases where glycopeptides have been prescribed for various reasons to treat infections caused by methicillin-sensitive staphylococci, their clinical effectiveness has been lower than that of β-lactams. The listed facts allow us to consider this group of antibiotics as suboptimal for the treatment of staphylococcal infections.

Resistance to glycopeptides among MRSA was not discovered for a long time, but since the second half of the 90s of the last century, reports began to be published about strains with a reduced level of sensitivity to them. The mechanism of stability has not been fully deciphered. It is difficult to estimate the frequency of distribution of such strains due to methodological difficulties in identifying them, however, it is obvious that the effectiveness of vancomycin is sharply reduced for the infections they cause. There are also isolated reports of the isolation of MRSA with high levels of resistance to vancomycin (transfer of resistance genes from enterococci).

Oxazolidinones

The only drug in the group is linezolid. It is highly active and effective against all staphylococci, regardless of resistance to other antibiotics. It is being considered as a serious alternative to glycopeptides in the treatment of infections caused by MRSA. Linezolid may be the drug of choice for the treatment of infections caused by strains of staphylococci with reduced sensitivity to glycopeptides.

Fluoroquinolones

The drugs in this group have different activity against staphylococci: ciprofloxacin and ofloxacin are relatively low, but clinically significant; levofloxacin, moxifloxacin, gemifloxacin and other new fluoroquinolones are more active. The clinical and bacteriological effectiveness of levofloxacin for staphylococcal infections is well proven. However, as stated above, associated resistance is often found in MRSA.

Drugs of other groups

Fusidic acid, co-trimoxazole and rifampicin are also effective against staphylococci. However, detailed clinical trials have not been conducted to evaluate them. Due to the fact that resistance to all of these drugs develops quite quickly, it is advisable to combine them (for example, co-trimoxazole and rifampicin). Such combinations are particularly promising for the treatment of mild MRSA infections.

Considering the above facts, it is obvious that when developing tactics for empirical treatment of staphylococcal infections in each specific department, it is necessary to take into account data on the frequency of MRSA spread.

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Enterococcus spp.

Enterococci were placed in a separate genus from streptococci in 1984. Within the genus Enterococcus, more than 10 species are distinguished, most of them extremely rarely cause human diseases. Among clinical isolates, 80-90% are E faecalis and 5-10% are E faecium, other species play a limited role. In ICU practice, enterococcal angiogenic infections, often associated with catheters, are the most important. In wound infections, enterococci, as a rule, are part of microbial associations and do not play a significant independent role. Their significance in the pathogenesis of intra-abdominal infections has not been precisely established, however, specific anti-enterococcal therapy does not improve treatment results. Enterococcal urinary tract infections are usually associated with catheters and resolve after their removal, either spontaneously or with the use of narrow-spectrum drugs.

Spectrum of natural sensitivity of Enterococcus spp. and acquired resistance. Of the known drugs, some ß-lactams, glycopeptides, rifampicin, macrolides, chloramphenicol, tetracyclines (doxycycline), nitrofurantoin and fluoroquinolones have anti-enterococcal activity. However, the clinical value of rifampicin, macrolides and chloramphenicol in the treatment of infections has not been determined. Tetracyclines, nitrofurantoin and fluoroquinolones are used only for the treatment of enterococcal urinary tract infections.

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ß-Lactam antibiotics

Among them, benzylpenicillin, aminopenicillins, ureidopenicillins (the greatest experience has been accumulated for piperacillin) and carbapenems have anti-enterococcal activity. All cephalosporins are devoid of it. It is important to note that the natural sensitivity to ß-lactams varies between the two main species of enterococci. E. faecalis is usually sensitive, while E. faecium is resistant. Neither ureidopenicillins nor carbapenems are superior to ampicillin. Drugs of this group exhibit only bacteriostatic activity against enterococci; to achieve a bactericidal effect they must be combined with aminoglycosides.

Glycopeptides

Glycopeptide antibiotics (vancomycin and teicoplanin) are traditionally considered as the drugs of choice in the treatment of enterococcal infections caused by strains resistant to ß-lactam antibiotics. However, glycopeptides, like ß-lactams, have only a bacteriostatic effect against enterococci. To achieve a bactericidal effect, it is advisable to combine glycopeptides with aminoglycosides.

Resistance to glycopeptides among enterococci began to be noted in the mid-80s of the last century; in recent years, such strains have appeared in Russia.

Oxazolidinones

Linezolid is the only drug available in Russia for the treatment of infections caused by vancomycin-resistant enterococci (VRE).

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Family enterobacteriaceae

The Enterobacteriaceae family includes more than thirty genera and several hundred species of microorganisms. Bacteria of the genera Escherichia, Klebsiella, Enterobacter, Citrobacter, Serratia, Proteus, Providencia, Morganella are of main clinical importance. There are numerous data confirming the etiological significance of the listed microorganisms. In each specific case of their isolation from primarily non-sterile areas of the human body, the assessment of their significance must be approached with all seriousness.

Antibiotic sensitivity spectrum of enterobacteria and acquired resistance. The natural sensitivity to antibiotics of individual members of the family varies. However, the basis of treatment is ß-lactams, fluoroquinolones and aminoglycosides.

ß-Lactams

Depending on the spectrum of natural sensitivity to them, enterobacteria are divided into several groups:

• Escherichia coli, Proteus mirabilis are resistant to all ß-lactam antibiotics, except natural and semi-synthetic penicillinase-stable penicillins. However, in ICUs, semisynthetic penicillins (amino-, carboxy- and ureidopenicillins) and first-generation cephalosporins are used little due to the widespread resistance to them. Thus, depending on the severity and nature of the infection (hospital or community-acquired), the drugs of choice for the empirical treatment of infections caused by microorganisms of the group under consideration are inhibitor-protected penicillins or cephalosporins of the II-IV generation.
• Klebsiella spp., Proteus vulgaris, Citrobacter diversus have a narrower spectrum of natural sensitivity. It is limited to cephalosporins of the II-IV generations, inhibitor-protected penicillins and carbapenems.
• Enterobacter spp., Citrobacter freundii, Serratia spp., Morganella morganii, Providencia stuartii are typical hospital pathogens, one of the most difficult groups to treat with ß-lactam antibiotics. The range of their natural sensitivity is limited to cephalosporins of the III-IV generations, carbapenems and drugs such as ticarcillin + clavulanic acid and piperacillin + tazobactam.

The basis for the treatment of enterobacter infections in the ICU is cephalosporins of the III-IV generations. For a long time it was believed that carbapenems, protected penicillins and cephalosporins (cefoperazone + sulbactam) were reserve drugs, but at present this approach should be revised. Due to the extremely widespread resistance mechanism in Russia in the form of extended spectrum ß-lactamases (ESIRs), which destroy all cephalosporins, the effectiveness of such drugs in the treatment of infections in ICUs has been sharply reduced.

Carbapenems (imipenem, meropenem and ertapenem) show maximum effectiveness against infections with Enterobacteriaceae producing ABIRS, while cefoperazone + sulbactam show less effectiveness. Currently, the ability to synthesize ESBLs is widespread mainly among pathogens of hospital infections. Moreover, it is impossible to predict their prevalence in a particular institution or even department without conducting special microbiological studies.

The basis of the tactics of empirical treatment of infections caused by ESBL producers is knowledge of their prevalence in a particular institution, as well as a clear distinction between community-acquired and hospital-acquired pathology.

• For community-acquired, even extremely severe infections, cephalosporins of III-IV generations are likely to be quite effective.
• For nosocomial infections, the use of cephalosporins is possible with a low incidence of ESBL in the institution, as well as in patients without the following risk factors: long-term hospitalization, previous antibiotic therapy, and concomitant diseases.
• For nosocomial infections in institutions with a high incidence of ESBL, especially in patients with the above risk factors, the drugs of choice are carbapenems or cefoperazone + sulbactam.

Drugs of other groups

Aminoglycosides and fluoroquinolones are significantly less effective in treating infections in the ICU than ß-lactams.

First of all, it should be noted that the use of aminoglycosides as monotherapy is inappropriate. Moreover, there is currently no evidence to support their use in combination with ß-lactams. Since the effectiveness of such combinations is not higher than monotherapy with ß-lactams.

Monotherapy of enterobacter infections in the ICU with fluoroquinolones is quite possible, although their use is less justified than ß-lactams. It should be noted that the “new” fluoroquinolones (levofloxacin, moxifloxacin, gemifloxacin) in their antimicrobial activity against enterobacteria and effectiveness are not superior to traditional drugs of this group (ciprofloxacin and ofloxacin). Almost complete cross-resistance is observed for all fluoroquinolones. Quite often, fluoroquinolones are used in combination with ß-lactams, but the validity of such combinations is also insufficient. A significant limitation for the use of fluoroquinolones is the very high frequency of associated resistance with ß-lactams; up to 50-70% of ESBL-producing enterobacteriaceae strains also exhibit resistance to fluoroquinolones.

Pseudomonas aeruginosa

Pseudomonas aeruginosa is part of the genus Pseudomonas. It, along with the genera Burkholderia, Comamonasu and some others, is in turn part of the family Pseudomonadaceae. Representatives of this taxonomic group are free-living, aerobic gram-negative rods, not demanding on cultivation conditions. They are classified as so-called non-fermenting bacteria (not capable of fermenting glucose). “Fermenting” microorganisms include the family Enterobacteriaceae (E. coli, etc.). Pseudomonadaceae are characterized by an oxidative mode of metabolism.

Antibiotic sensitivity spectrum

Some ß-lactams, aminoglycosides, fluoroquinolones, and polymyxin B have clinically significant antipseudomonal activity.

ß-Lactams

Carbapenem antibiotics exhibit the greatest activity against P. aeruginosa (meropenem in vitro is somewhat more active than imipenem, and ertapenem is inactive). Next in descending order of activity are IV generation cephalosporins (cefepime), aztreonam, III generation cephalosporins (ceftazidime, cefoperazone), ureidopenicillins (primarily piperacillin), ticarcillin and carbenicillin. It must be emphasized that common cephalosporins (cefotaxime and ceftriaxone) are practically devoid of antipseudomonal activity.

Acquired resistance to ß-lactams is a very common phenomenon among P. aeruginosa. Its main mechanisms are hyperproduction of its own chromosomal ß-lactamases, the development of methods that ensure the removal of antibiotics from the internal environment of bacterial cells, and a decrease in the permeability of external structures as a result of the complete or partial loss of porin proteins. Acquired ß-lactamases of various groups (most often the OXA group) are also common among P. aeruginosa.

The diversity of resistance mechanisms results in a significant diversity of possible phenotypes. The vast majority of strains circulating in ICUs are currently resistant to carbenicillins and piperacillin, rendering these drugs almost completely irrelevant. Quite often, P. aeruginosa remains sensitive to the combination of piperacillin + tazobactam.

Ceftazidime and cefepime are currently considered the main antipseudomonal drugs. There is incomplete cross-resistance between them. There are strains that are resistant to one of these antibiotics, but sensitive to another. Among pseudomonads, resistance to carbapenems is the least common, and there is also no complete cross-resistance between imipenem and meropenem. There may be cases where the microorganism is not sensitive to carbapenems, but the use of ceftazidime or cefepime is effective. In such a situation, planning empirical therapy for pseudomonas infections is possible only on the basis of local data on the characteristics of antibiotic resistance of microorganisms in a particular institution.

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Aminoglycosides

All aminoglycosides available in Russia (gentamicin, tobramycin, netilmicin and amikacin) exhibit approximately the same activity against P. aeruginosa. The MIC of amikacin is slightly higher than that of other representatives of the group, but its doses and, accordingly, concentrations in blood serum are also higher. In strains of P. aeruginosa common in Russia, resistance to gentamicin and tobramycin is most common, and resistance to amikacin is rare. The patterns of cross-resistance to aminoglycosides are quite complex and in practice almost any variant can occur. Having data on the sensitivity of a microorganism to three aminoglycosides, it is impossible to predict with complete certainty the sensitivity to the fourth.

Aminoglycosides are not used as monotherapy for pseudomonas infections. However, in contrast to enterobacter diseases, for infections caused by P. aeruginosa, the use of combinations of ß-lactams and aminoglycosides is quite widespread and quite justified (especially against the background of neutropenia).

Fluoroquinolones

Among all available fluoroquinolones, ciprofloxacin has the greatest activity against P. aeruginosa. However, pharmacodynamic calculations indicate that to obtain a reliable clinical effect, its daily dose must be more than 2.0 g, which is higher than the permissible values.

Multiple resistance

An extremely difficult problem for antibacterial therapy is the so-called pan-resistant strains of P. aeruginosa. They are resistant to all ß-lactams, aminoglycosides and fluoroquinolones. Such strains, as a rule, remain sensitive only to polymyxin B. One of the possible approaches to the treatment of infections caused by such microorganisms may be a quantitative assessment of sensitivity and the selection of a combination of two or more antibiotics that demonstrate the lowest MIC values, but the effectiveness of such an approach in the clinic insufficiently studied.

Duration of antibacterial therapy

Antibacterial therapy is carried out until persistent positive changes in the patient’s condition are achieved and the main symptoms of infection disappear. Due to the absence of pathognomonic signs of bacterial infection, absolute criteria for its cessation are difficult to establish. Usually, the issue of stopping antibiotic therapy is decided individually based on a comprehensive assessment of changes in the patient’s condition. However, the general criteria for the sufficiency of antibacterial therapy are as follows:

• disappearance or reduction in the number of microorganisms in material obtained by invasive method from the main source of infection,
• negative blood culture results,
• absence of signs of a systemic inflammatory response and infection-related organ dysfunction,
• positive dynamics of the main symptoms of infection,
• stable normalization of body temperature (maximum daily

The persistence of only one sign of bacterial infection (fever or leukocytosis) is not considered an absolute indication for continued antibiotic therapy. Since studies have shown that during the stay of patients in the ICU on mechanical ventilation, the achievement of normal temperature, the disappearance of leukocytosis and sterilization of the tracheal mucosa are unlikely even with adequate antibacterial therapy. Isolated subfebrile body temperature (maximum daytime 9/l) without a shift of the leukocyte formula to the left and other signs of bacterial infection.

The usual duration of antibacterial therapy for hospital infections of various localizations is 5-10 days. Long periods are undesirable due to the development of possible complications of treatment, the risk of selection of resistant strains and the development of superinfection. In the absence of a stable clinical and laboratory response to adequate antibacterial therapy within 5-7 days, additional examination (ultrasound, CT, etc.) is necessary to search for complications or a source of infection in another location.

Longer periods of antibacterial therapy are necessary for infections of organs and tissues, where therapeutic concentrations of drugs are difficult to achieve, therefore, there is a higher risk of persistence of pathogens and relapses. Such infections primarily include osteomyelitis, infective endocarditis, and secondary purulent meningitis. In addition, for infections caused by S. aureus, longer courses of antibiotic therapy (2-3 weeks) are also usually recommended.

One of the great discoveries of the twentieth century in medicine is the discovery of antibiotics.
The significance of the era of antibiotics can be shown by a specific example, especially understandable to pediatricians: the mortality rate from pneumonia in children under 3 years of age before the use of antibiotics was 30%, in children over 3 years of age - 15%, mortality from lobar pneumonia - 84.5% , it was an almost absolutely fatal disease.

The use of modern antibiotics makes it possible to prevent mortality from community-acquired pneumonia.

Antibiotic– a substance of microbial, animal, or plant origin that can inhibit the growth of microorganisms or cause their death.

In addition to antibiotics, there are a significant number of drugs of various pharmacological groups, obtained synthetically, which have an antimicrobial effect: sulfonamides, drugs based on trimethoprim, derivatives of nitrofuran, 8-hydroxyquinolone, quinoxaline, fluoroquinolones, nitroimidazoles, etc.

Antibiotic therapy is the treatment of patients with infectious diseases caused by microorganisms using drugs that specifically act on these microorganisms.

.Classification:

1. Taking into account the mechanism of action, antibiotics are divided into three main groups:

- inhibitors of microorganism cell wall synthesis: penicillins, cephalosporins, monobactams, carbapenems, glycopeptides (vancomycin, teicoplanin), bacitracin, cycloserine;

- antibiotics that disrupt the molecular organization and functions of cell membranes: fosfomycin, polymyxin, nystatin, levorin, amphotericin;

- antibiotics that suppress the synthesis of protein and nucleic acids:
a) inhibitors of protein synthesis at the ribosome level: chloramphenicol, tetracyclines, macrolides, lincomycin, clindamycin, aminoglycosides, fusidine;
b) RNA polymerase inhibitors (rifampicin)

2.-Based on their chemical structure, the following groups of antibiotics are distinguished::

- beta-lactams; aminoglycosides; chloramphenicol; tetracyclines; macrolides; azalides; lincomycin; fusidine; ansamacrolides (rifampicin); polymyxins; polyenes.

3. Separation of antibiotics according to the spectrum of antimicrobial action:

a) drugs that act primarily on gram-positive(+) bacteria.
This group includes benzylpenicillin, phenoxymethylpenicillin, bicillins, penicillinase-resistant penicillins (oxacillin, dicloxacillin), first generation cephalosporins, macrolides, vancomycin, lincomycin;

b) antibiotics wide range actions taken towards
G (+) and G(-) microorganisms: chloramphenicol, tetracyclines, aminoglycosides, broad-spectrum semisynthetic penicillins (ampicillin, carbenicillin, azlocillin) and second-generation cephalosporins (cefuroxime);

c) antibiotics with primary activity against G (—) bacteria: polymyxins, third generation cephalosporins;

d) anti-tuberculosis antibiotics: streptomycin, rifampicin, florimycin;

e) antifungal antibiotics: nystatin, levorin, griseofulvin, amphotericin B, intraconazole, ketocanazole, miconazole, fluconazole, flucytozyme, clotrimazole.

4. Depending on the type of action on the microbial cell, antibiotics are divided into 2 groups:

- bactericidal: penicillins, cephalosporins, aminoglycosides, rifampicin, polymyxins;

- bacteriostatic: macrolides, tetracyclines, lincomycin, chloramphenicol.

Principles of antibiotic therapy:

— the main principle is the prescription of an antibacterial drug in accordance with the sensitivity of the pathogen;
— the antibiotic must create a therapeutic concentration at the site of infection;
- choosing an antibiotic with maximum effectiveness and minimal toxicity.

Antibiotics are only effective for bacterial infections.

Indications for prescribing antibiotics are:

- prolonged (more than 3 days) fever,
- severe intoxication,
— the presence of a corresponding clinical picture and hematological changes caused by bacterial or atypical flora.

Evaluating the effect and changing the drug.

It makes sense to continue treatment with the starting antibiotic only when the effect occurs, which in acute diseases occurs 36-48 hours from its start.

The full effect is a drop in temperature below 38°C, an improvement in general condition, the appearance of appetite, and a decrease in clinical manifestations. This indicates the sensitivity of the pathogen to the drug and allows you to continue taking it.

Lack of effect - preservation of febrile temperature with worsening of the condition or increase in pathological changes in the lesion and general disorders (shortness of breath, toxicosis, etc.) requires a change in antibiotic.

Duration of therapy should be sufficient to suppress the vital activity of the pathogen so that its inactivation and elimination from the body is carried out by immunological mechanisms.

For acute infection, it is sufficient to continue treatment for 2 days after the temperature drops, pain disappears, etc.

However, the duration of therapy is determined not only by the immediate clinical effect, but also by the need to eradicate the pathogen (complete destruction). For many processes, the optimal duration of treatment has been established experimentally - 7-10 days.

To summarize The above shows that medicine has a large arsenal of antibacterial drugs. But despite this, it is sometimes difficult to choose an effective antibiotic.

Among the reasons for lack of effectiveness in children are the following:

— increased resistance of microorganisms to traditional antibacterial drugs used in pediatrics (penicillins, macrolides);

— an increase in the number of children with defects in protective factors who are not capable of completely eliminating the pathogen from the body during treatment and who are a potential source of the spread of resistant pathogenic strains (especially in children's groups);

— the emergence of new types of pathogens and their associations;

— the difficulty of choosing an antibacterial drug due to the limited range of antibacterial drugs approved for use in pediatric practice.

Only rational use of antibiotics can reduce the growth of microbial resistance and thereby increase the effectiveness of antibiotic therapy.

Indications and choice

Feasibility of therapy. Antibiotics are only effective for bacterial infections; unfortunately, they are received by 50-80% of patients with uncomplicated acute respiratory viral infections and the majority of patients with diarrhea caused by viruses or resistant microbes.

By prescribing an antibiotic without proper justification, the doctor not only increases the risk of side effects and disruption of the microbial biocenosis, but also contributes to the spread of drug resistance. Thus, over the past 10-15 years, resistance of pneumococci to penicillins has spread in many countries of the world, reaching 40-80%. It is also important that the doctor, having not received an effect from the antibiotic in this case, often resorts to backup drugs.

The most important step when prescribing antibiotics is deciding whether they are indicated for a given patient. And if an antibiotic is prescribed with incomplete confidence in the bacterial nature of the disease, it is important to clarify this issue and, if the initial suspicion is not confirmed, cancel it.

Choice of drug. The choice of drug should be based on its antibacterial spectrum and data on the drug sensitivity of the pathogen. Since in acute illness the choice is made without these data (they take time to obtain), it is based on recommendations for empirical initial therapy, taking into account the likely etiology of the disease. The correct choice of antibiotic is indicated by the rapid onset of the treatment effect.

In chronic diseases, as well as in severe, especially hospital infections, isolation of the pathogen increases the chances of success. The same applies to cases of severe illness in the absence of effect from initial therapy.

The choice of drug should also take into account its ability to penetrate the affected organ: for example, a drug excreted by the liver will not be suitable for the treatment of kidney disease.

First choice drugs are used in cases where there is no reason to think about drug resistance, primarily in community-acquired infections. Where resistance is likely (nosocomial infection, previous antibiotic therapy), treatment should begin with 2nd choice drugs, increasing the chances of affecting strains that have developed resistance to 1st choice drugs. It would seem logical to start with 2nd choice drugs in all patients in order to increase the percentage of effectiveness; but it is precisely this tactic, which, unfortunately, is not uncommon - the main reason for the spread of resistance, depriving drugs of their benefits.

3rd choice drugs (reserve) are used only in cases of severe multidrug resistance in hospitals; strict control over their use (only by decision of the council) prevents the formation of resistance in hospital flora to them.

Age and localization of the process. For each localization of a microbial process, there is a fairly small list of probable pathogens, which allows us to assume a likely etiology and make a rational choice of antibiotic for initial therapy and provide for a replacement in case of failure. The nature of the flora changes with age, which is largely explained by immunological factors. Therefore, recommendations for empirical starting therapy for the same disease in infants and older children differ not only in terms of doses, but also in drugs.

Monotherapy or combination therapy? Monotherapy is more preferable; combinations of drugs are used to expand the antibacterial spectrum in the absence of data on the pathogen, as well as to overcome or prevent drug resistance (for example, in tuberculosis).

Doses and frequency of administration

For each drug, the manufacturer indicates the optimal range of daily doses and frequency of administration. These data are based on the levels of antibiotic concentrations achieved in the blood, which is important, for example, for the treatment of sepsis. When treating tissue infections, the drug concentrations created in the tissues and the time during which it exceeds the minimum inhibitory concentration (MIC) for a given pathogen are of greater importance.

Increasing the tissue concentration of β-lactam drugs (penicillins, cephalosporins) and macrolides does not increase their bactericidal activity, therefore, if they are ineffective, increasing the dose is not advisable; it is better to use another drug to which the pathogen is sensitive. For this group of drugs that have a short antibiotic effect (no growth of microorganisms after the end of antibiotic exposure), it is important to maintain tissue concentration levels above the MIC for 45-55% of the treatment time. For macrolides with a long elimination period, this is achieved with a small frequency of administration (2-3 times a day, and for azithromycin - 1 time a day). When using β-lactam drugs with a short half-life, a large (3-4 times a day) frequency of administration is usually recommended. It has been shown, however, that with double administration of 1/2 the currently recommended daily doses of these drugs, a higher peak concentration of drugs in tissues is achieved and it remains at a level above the MIC of sensitive bacteria for 60-70% of the time, which is sufficient for obtaining clinical and bacteriological effects.

The bactericidal activity of aminoglycosides and fluoroquinolones increases in parallel with the increase in their peak concentration in tissues, which serves as the basis for the administration of even higher single doses - the entire daily dose at once. These drugs have a pronounced post-antibiotic effect, which makes their effect independent of the time the concentration is maintained above the MIC. A single administration of the entire daily dose is also recommended for drugs that accumulate in cells (azithromycin, rifampicin) or have a long half-life (ceftriaxone).

This tactic is safe, since toxicity (in particular, ototoxicity) depends on the daily dose, i.e. from the average concentration of the drug.

These data obtained in recent years have made it possible to revise recommendations on the frequency of administration, which is important for both injection (reducing trauma) and oral drugs (increasing compliance - adherence to the prescribed regimen of taking the drug). Reducing the frequency of administration of most antibiotics (at the same daily doses) does not reduce, but often increases, the effectiveness of treatment. Controlled trials and the experience of many clinics and hospitals allow us to recommend 2-fold administration of antibiotics for almost any respiratory disease.

For the same reason, when administered intravenously, a simultaneous infusion is preferable, unless, of course, the instructions require slow or drip administration of the drug used. And only in case of sepsis is the constancy of the concentration of the antibiotic in the blood important, which is achieved by more frequent - 4 times intramuscular or intravenous drip - administration.

Routes of administration

In pediatric practice, the main route of drug administration is oral, as it is the least traumatic. The preference for parenteral administration has literally led to an injection epidemic - children receive 20-40, or even 75 injections during a course of treatment! The use of oral medications allows 90-95% of patients to avoid injections at all.

Among oral medications, children's forms in the form of syrups, suspensions and powders or granules compare favorably (not only with good taste, but also with dosage accuracy).

Of the parenteral routes, intravenous is more acceptable as it is less traumatic in the presence of a peripheral venous catheter; Widespread use of a central venous catheter is unacceptable due to the risk of sepsis. The intramuscular route should be used only for a short time and after the onset of the effect of treatment, switch to oral administration of a similar drug. This step-by-step tactic reduces the number of injections and the associated mental trauma.

The aerosol route has limited use due to poor penetration and the lesion is in the lung; it is used only when long-term therapy of a pulmonary process is necessary. The introduction of antibiotics into the lesion, which makes it possible to increase its local concentration, is indicated for purulent processes. Most often, aminoglycosides and 2nd and 3rd generation cephalosporins are used for this purpose; a single daily dose of the drug is administered.

The use of depot drugs (for example, benzathine-benzylpenicillin) is limited to the treatment of diseases caused by highly sensitive pathogens (syphilis, group A streptococcus).

Evaluating the effect and changing the drug

It makes sense to continue antibacterial treatment only if clinical improvement occurs. In acute illness, the effect should be expected within 36-48 hours from the start of treatment. The following situations can be distinguished in assessing the effect.

The full effect - a drop in temperature below 38°C, an improvement in general condition, the appearance of appetite, a decrease in clinical manifestations and changes in the lesion indicates the sensitivity of the pathogen to the drug and allows you to continue the same treatment.

Partial effect is a decrease in the degree of toxicosis, improvement in general condition and appetite, a decrease in the severity of the main clinical symptoms (for example, shortness of breath, stool frequency, meningeal signs, pain), the absence of negative dynamics in the site of inflammation while maintaining febrile temperature and some symptoms. It is usually observed in the presence of a purulent cavity; it does not require a change in antibiotic; the full effect occurs when the abscess is emptied or opened. Fever (meta-infectious) is associated with an immunopathological process, the effect is achieved by prescribing anti-inflammatory drugs.

Lack of effect - persistence of febrile temperature with deterioration of the condition and/or increase in pathological changes in the source of inflammation and general disorders (shortness of breath, toxicosis, symptoms from the central nervous system, etc.) - requires a change in antibiotic.

The ineffectiveness of the antibiotic may be associated both with the resistance of the pathogen to it and with its limited penetration into the lesion: the accumulation of pus reduces blood flow and suppresses phagocytosis due to local hypoxia and acidosis, drainage dramatically changes the situation in a favorable direction. Pus reduces the activity of aminoglycosides, macrolides, and lincomycin due to a decrease in the pH of the environment and/or increased binding of the antibiotic to tissue breakdown products.

Duration of treatment

The duration of therapy should be sufficient to suppress the activity of the pathogen and allow immunological mechanisms to complete its elimination or inactivation. For chronic infections, this may take many months; for acute infections, 2 days may be sufficient after the temperature drops, pain disappears, exudate drains, etc. However, the duration of therapy is determined not only by the immediate effect, but also by the frequency of long-term adverse effects and relapses.

Antibacterial prophylaxis

Indications for it are few; antibiotics are administered once 1-2 hours before operations on the intestines, heart, or dentistry. Chemoprophylaxis of tuberculosis infection in contact tuberculin-negative children is effective. Preventive treatment is carried out for patients with rheumatism, persons with immunodeficiency, transplant recipients, contacts of whooping cough, meningococcal or H. influenzae type b infections, with possible exposure to HIV, victims of sexual violence.

However, the widespread use of antibiotics for the prevention of bacterial diseases, for example, during respiratory viral infections, is not only ineffective, but also dangerous, because suppresses protective opportunistic autoflora. Bacterial superinfections in children with ARVI who received antibiotics in the hospital are observed 2 times more often than in those who did not receive them, due to the resistance of the pathogen, and treatment is often difficult. A gentle attitude towards opportunistic autoflora is one of the most important arguments for the preventive use of antibiotics.

Antibiotics in childhood

The physiological characteristics of children lead to changes in the pharmacokinetics of antibiotics, which affects their use. The larger volume of extracellular fluid in a child requires the use of larger doses of drugs per 1 kg of body weight compared to adults. The use of a number of drugs in children is prohibited due to their toxicity. Thus, tetracyclines in children under 8 years of age disrupt bone growth and stain teeth, and fluoroquinolones disrupt the growth of cartilage tissue (in experiments on puppies).

The use of antibiotics in newborns also requires some modification compared to older children. This is due to a decrease in glomerular filtration, as well as the immaturity of the enzymatic systems of the liver. In the first week of life, smaller daily doses of most antibiotics are administered, reducing the frequency of their administration. For those born weighing more than 2500 g, the daily doses used in full-term newborns are reduced by another 1/4-1/3, usually due to more rare administration of the same single doses. For children aged 0-7 days (and those born weighing less than 1200 g - at the age of 0-28 days), the daily dose is reduced by another 1/4-1/3 compared to older children born with the same weight, also for due to lower frequency of administration and/or single dose.

Drugs with high affinity for plasma protein (ceftriaxone, sulfonamides) can increase jaundice; chloramphenicol (chloramphenicol) causes “gray disease” in newborns due to excessive accumulation and toxic effects on the myocardium.

Antibiotics in special groups of patients

In patients with reduced glomerular filtration, reduce the dose of drugs that are excreted mainly by the kidneys in the active form. This is achieved by lengthening the intervals between administrations of the drug, and in severe cases, by reducing single doses. There is no need to reduce the doses of azithromycin, doxycycline, lincomycin, clindamycin, ceftriaxone, cefoperazone, chloramphenicol, isoniazid, rifampicin.

Patients with a slight decrease in glomerular filtration (safety more than 50%) can receive full doses of all penicillins, erythromycin, metronidazole, cefazolin, cefuroxime, cefotaxime, cefoxitin, fluoroquinolones, acyclovir, ganciclovir, amphotericin B, fluconazole, ketoconazole. With a greater degree of renal dysfunction, the doses of these drugs are reduced by 25-75%. Doses of aminoglycosides and vancomycin are reduced even with a slight decrease in glomerular filtration rate.

If liver function is impaired, do not use erythromycin, spiramifin, doxycycline, tetracycline, co-trimoxazole, reduce the doses of cefoperazone, aztreonam, other macrolides, lincomycin, chloramphenicol and metronidazole, as well as anti-tuberculosis drugs.

In patients undergoing hemodialysis, one has to consider removing part of the antibiotic and administering it additionally. Most of all (more than 50%) aminoglycosides, many cephalosporins, imipenem, and acyclovir are removed. Penicillins, cefaclor, metronidazole, vancomycin are removed by 25-50%, and to a lesser extent - oxacillin, macrolides, tetracyclines, cefoperazone, cefixime, amphotericin B, and fluoroquinolones. Peritoneal dialysis does not lead to significant washout of most drugs, with the exception of aminoglycosides, cefuroxime and vancomycin (by 15-25%).

Data on the compatibility of antibiotics with other drugs should also be taken into account - they are indicated in the instructions for use of the drugs.

Possibility of side effects

All antibiotics can cause side effects. Allergic reactions in the form of a rash are more common, and their reoccurrence is more likely in people who have previously had drug rashes, although up to 85% of people who have reacted to penicillin tolerate repeated courses without complications. Allergic reactions occur more often when antibiotics are used in patients without bacterial infections; the latter are accompanied by the release of cAMP, cGMP and other mediators that prevent the allergic reaction.