Prevalence, etiology and general treatment approaches
Infections of the upper respiratory tract (URT) and ENT organs are among the most common diseases. In the structure of overall morbidity in Moscow, they account for approximately 19% and are in second place among all pathologies [1].
Approximately 5–15% of adults and 5% of children suffer from some form of sinusitis [1]. In Russia, about 10 million people suffer from acute sinusitis annually [2], and at least 80% of them are people of working age [3]. It is also one of the most widespread diseases in children.
The share of acute otitis media in the structure of diseases of the ENT organs accounts for 20–30% [4, 5]. In Europe, its incidence in the adult population is 1–5% per year [6]. In the United States, acute otitis media occurs annually in 10 million people [5], affecting about 14% of the population [7]. During the first year of life, 62% of children experience at least one episode of the disease; by the age of two to three years – 80–94% [8, 9]. Acute otitis media occupies a leading position in the structure of seeking medical care in pediatrics, accounting for 33% of all doctor visits [8,9].
The main clinical manifestation of tonsillopharyngitis is a sore throat, which is observed in an adult on average two to three times a year [10]. Pharyngitis caused by group A beta-hemolytic streptococcus is one of the most common bacterial infections in children under two years of age. Chronic tonsillitis occurs in 2–3% of children aged 3 years, 6.5% – 5–6 years old, 12–13% – 10–12 years old, and 25–35% of people aged 18–20 years [11]. Its prevalence among frequently ill children aged 2–6 years reaches 43% [12].
Infections of the upper respiratory tract and ENT organs are potentially dangerous in terms of the development of serious complications and deaths, the risk of which increases significantly in the case of irrational treatment of the primary disease. Thus, tonsillitis and pharyngitis can be complicated by infections of neighboring organs (otitis media, sinusitis, bronchitis), and also cause severe regional complications (peritonsillar, lateral pharyngeal and retropharyngeal abscesses, etc.), requiring emergency surgical interventions, and systemic complications - rheumatism, glomerulonephritis, vasculitis, etc. Acute otitis media is one of the leading causes of meningitis, brain abscess and thrombosis of the asigmoid sinus [4]. Sinusitis can lead to the development of severe orbital and intracranial complications.
Infections of the upper respiratory tract and ENT organs are also associated with significant financial losses. For example, in the USA, direct and indirect costs associated with acute otitis media exceed $3.5 billion per year [13], and $3.5 billion is spent annually on the treatment of acute bacterial sinusitis [14], including in children up to 12 years – 1.8 billion [15]. In Russia, the average duration of temporary disability for acute sinusitis is 11.6 days [16]. Economic losses caused only by temporary disability are estimated at 232 million US dollars, or 0.15% of the gross domestic product of the Russian Federation [16]. Thus, the correct choice of treatment for infections of the upper respiratory tract and ENT organs is, along with clinical, of great economic importance. Adequate treatment of these infections is also an important factor in the prevention of bacterial resistance.
Unfortunately, the widespread increase in the resistance of the main causative agents of infections of the upper respiratory tract and ENT organs to many antibacterial agents, including first-line drugs, significantly limits the choice of antibiotics for empirical therapy. For example, the spread of beta-lactamase-producing strains of H. influenzae and M. catarrhalis and the emergence of penicillin-resistant pneumococci are already calling into question the legality of using amoxicillin as a first-line drug for acute otitis media and other community-acquired infections [17].
In addition, in recent years there have been changes in the etiological structure of infections of the upper respiratory tract and ENT organs, which necessitates a revision of approaches to the management of patients with infections of this localization. First of all, this is due to the increasing role of “atypical” bacterial pathogens (M. pneumoniae, C. pneumoniae) in the etiology of acute respiratory diseases (ARI), laryngotracheitis and other respiratory tract infections, especially in young people and children [18]. For example, in a randomized study whose participants included 353 children aged 1 to 14 years with recurrent acute respiratory infections and 208 healthy children (control group), “atypical” pathogens were identified in 54% of patients in the main group compared to 3.8% children from the control group (p < 0.0001) [18]. This study also showed that short-term (within a month) and long-term (within six months) clinical benefit was observed significantly more often in patients receiving azithromycin along with symptomatic therapy than in children receiving symptomatic therapy alone. Moreover, the long-term clinical effect of azithromycin (reduction in the frequency of relapses) was expressed in infections caused not only by “atypical” pathogens, but also by other pathogens. The results of the study led to the conclusion that “atypical” bacteria play a fairly large role in the occurrence of recurrent respiratory tract infections in children and that long-term therapy with azithromycin can not only significantly improve the course of an acute episode of the disease, but also reduce the risk of relapses.
Another recent study showed that, if not adequately treated, acute tonsillopharyngitis in children associated with atypical bacteria can lead to unfavorable outcomes and is associated with a high risk of relapse [19]. These data make us more critical of modern recommendations, which do not support the use of antibiotics in most patients with acute infections of this localization, and contribute to increasing the role of macrolides in their therapy.
Currently, azithromycin has actually already acquired the status of a first-line antibiotic for the treatment of infections of the respiratory tract and ENT organs, despite the fact that in most recommendations it is given the position of a drug alternative to beta-lactams [20]. This is due to the favorable pharmacological properties of azithromycin, proven effectiveness and safety, and the increasing etiological role of atypical pathogens.
Rationale for the feasibility of using azithromycin for infections of the respiratory tract and ENT organs from a pharmacological point of view
Like other macrolides, azithromycin is active against the main causative agents of infections of the respiratory tract and ENT organs (S. pneumoniae, S. pyogenes, M. catarrhalis), including atypical pathogens (mycoplasma, chlamydia). Its advantage over other macrolides is its clinically significant activity against the common causative agent of acute otitis media and acute bacterial sinusitis, H. influenzae. Like other macrolides, azithromycin has a bacteriostatic effect, but due to its unique pharmacokinetic properties it is capable of creating very high interstitial and intracellular concentrations and, accordingly, has a bactericidal effect, including on pathogens located inside cells [21].
Azithromycin is characterized by post-antibiotic effects against S. pyogenes, S. pneumoniae, H. influenzae, L. pneumophila. In terms of the duration of the post-antibiotic effect against a number of microorganisms, for example, H. influenzae and Legionella pneumophila, it is superior to clarithromycin [22, 23]. The effect of azithromycin is enhanced by its anti-inflammatory and immunomodulatory properties [24].
Azithromycin differs from erythromycin and other macrolides in improved pharmacokinetic properties: it is superior to other antibiotics of this group in acid resistance (300 times higher than erythromycin), is more consistently absorbed from the gastrointestinal tract and has greater bioavailability. The high lipophilicity of azithromycin determines its wide distribution in the body (volume of distribution - 31 l/kg) and good penetration into tissues and biological fluids. Its concentrations in various tissues after a single administration are 20–1000 times higher than those in blood plasma [25, 26]. Very high concentrations of the drug are created in the respiratory tract and ENT organs: in bronchial secretions, lungs, alveolar fluid, tonsils, adenoids, middle ear and paranasal sinuses [27, 28]. They far exceed the minimum inhibitory concentrations of the antibiotic for the most common pathogens that cause infections in the corresponding localization.
Azithromycin is significantly superior to erythromycin in its ability to penetrate into the paranasal sinuses [29]. Its maximum concentrations in the mucous membrane of the maxillary sinus are created within two hours after administration and significantly exceed the level of the antibiotic in the blood serum. Research conducted at the L.S. Strachunsky showed that two hours after taking 500 mg of azithromycin, its concentrations in the mucous membrane of the maxillary sinus were eight times higher than those in the blood serum, while the maximum concentrations of erythromycin were approximately three times lower than serum concentrations [30]. In a placebo-controlled study in animals with experimental rhinosinusitis, azithromycin, creating high concentrations at the site of infection, ensured rapid clearance of bacteria and disappearance of inflammation [31]. In contrast, the new fluoroquinolone with bactericidal action, moxifloxacin, which creates low concentrations in the lesion and has a short post-antibiotic effect, had little effect on bacterial clearance and the inflammatory process [31].
Azithromycin very quickly reaches high concentrations in the tonsils and adenoids. 2–24 hours after administration, its concentrations in the tonsils exceed the MIC for S. pyogenes by 30 times [30]. The half-life of azithromycin from tonsil tissue reaches 3.2 days [32]. In children aged two to eight years who received a three-day course of treatment with an azithromycin suspension at a dose of 10 mg/kg/day, the level of the antibiotic in the tonsils and adenoids four days after completion of therapy was more than 900 times higher than its serum concentrations [26]. In patients with recurrent or chronic tonsillitis, after oral administration of azithromycin at a dose of 250 mg twice daily, high concentrations of the drug in the tonsils persisted for seven days [26].
High levels of azithromycin are detected in the mucous membranes of the ethmoid sinus and in the tympanic cavity [26]. In children with otitis media, within 24 hours after the start of therapy, azithromycin concentrations in the middle ear reach 8–9 mg/kg [33].
Data on antibiotic concentration levels in the respiratory tract and ENT organs obtained in pharmacokinetic studies are summarized in the table.
Azithromycin is metabolized to a small extent with the formation of inactive metabolites [36]. The drug is excreted primarily in bile. Elimination of azithromycin has a biphasic nature, the half-life from the body is 35–79 hours [37, 38] and does not change with renal and liver failure and cirrhosis of the liver [39, 40].
Favorable pharmacokinetic properties make it possible to take azithromycin once a day in short courses of three to five days, and for some infections even as a single dose. No significant differences in the pharmacokinetics of the antibiotic (accumulation in macrophages, tissue and cellular concentrations) were found when using three- and five-day courses of treatment [41].
The unique regimen of azithromycin provides it with advantages over other antibiotics in terms of patient adherence to therapy. This is facilitated by the possibility of using it regardless of food intake. Although azithromycin is recommended to be taken before meals, several targeted studies have demonstrated that food does not significantly affect the bioavailability of this antibiotic in various dosage forms [42]. The advantage of azithromycin in pediatrics is the favorable organoleptic properties of the pediatric suspension of the drug [43, 44].
Azithromycin is well tolerated. Adverse reactions with its use rarely develop. The incidence of adverse drug reactions in adults and children is about 9% [45], while with erythromycin treatment it reaches 30–40% [46]. Serious adverse reactions with the use of azithromycin in clinical studies were recorded extremely rarely, and their cause-and-effect relationship with the drug has not been definitively established. According to the results of meta-analyses, the rate of azithromycin discontinuation due to adverse reactions is 0.7% for lower respiratory tract infections and 0.8% for upper respiratory tract infections [47, 48].
Azithromycin has low allergenic potential. Allergic reactions are observed in less than 1% of patients, while when treated with penicillins they develop in 10% of cases, and with cephalosporins in 4% [46]. The most common side effects are azithromycin dyspeptic disorders, the incidence of which, according to several controlled clinical studies, ranges from 6 to 9% [49]. Thus, in pediatric clinical studies, diarrhea was observed in 1–6% of participants, abdominal pain in 1–4%, nausea in 0.5–2%, and vomiting in 1–6%. Elevated liver enzyme levels occurred in 0–1% of children receiving azithromycin versus 2–4% of children receiving erythromycin [49].
The absence of a pronounced effect on the enzymes of the cytochrome P450 system in the liver provides azithromycin with a low potential for clinically significant drug interactions, which determines its fairly high safety when used in combination with other drugs. In this indicator, azithromycin is superior to most macrolides, which, in terms of their effect on cytochrome P450, are arranged in the following order: clarithromycin > erythromycin > roxithromycin > azithromycin > spiramycin [50].
The use of azithromycin is quite safe during pregnancy. It is the only semi-synthetic macrolide classified by the FDA as category B. This category includes drugs that do not have an adverse effect on the fetus and the course of pregnancy in animal experiments. There are also clinical data confirming the safety of azithromycin in pregnant women [29].
The use of macrolides for empirical treatment of infections of the respiratory tract and ENT organs is also justified from the point of view of the low level of resistance to them in common pathogens of this localization in Russia. According to the multicenter study PeGaS-1 (2000), the frequency of pneumococcal resistance to azithromycin is 5%, to erythromycin – 6%, to clarithromycin – ranges from 2 to 13% [24]. Moreover, according to Japanese authors, azithromycin remains active against pneumococci resistant to other macrolides [51]. “Overcoming” the low level of resistance of microorganisms is apparently associated with the pharmacokinetic properties of azithromycin.
Evidence of the effectiveness of azithromycin for infections of the upper respiratory tract and ENT organs
The high effectiveness of azithromycin for infections of the upper respiratory tract and ENT organs in adults and children has been proven in controlled clinical studies. Between 1991 and 2001, the effectiveness of azithromycin in infections of the upper respiratory tract and ENT organs was studied in at least 29 randomized clinical trials, which included 7240 patients, including 4263 children [52]. Along with five-day courses of treatment, shorter treatment regimens have also been studied to improve adherence to treatment and reduce its cost. Three-day courses of azithromycin therapy were compared with 7–14-day courses of clarithromycin, roxithromycin, phenoxymethylpenicillin, amoxicillin/clavulanate, and cefaclor. In most studies, a short course of azithromycin was not inferior in clinical and bacteriological effectiveness to standard courses of comparator drugs, and in some it was even superior to them.
Currently, azithromycin is the only antibiotic approved by the FDA for short-term use in acute bacterial sinusitis. The basis for approval was the results of a multicenter, randomized, double-blind trial involving 936 patients [53]. It compared the effectiveness and safety of two treatment regimens: azithromycin 500 mg once daily for 3 or 6 days and amoxicillin/clavulanate 625 mg 3 times daily for 10 days. The effectiveness of all treatment regimens was the same, however, when treating with amoxicillin/clavulanate, side effects were observed more often (51.1%) than when using 3-day (31.1%; p < 0.001) or 6-day courses of azithromycin (37.6 %; p < 0.001). There were also more patients in the amoxicillin/clavulanate group who dropped out of the study (n = 28) due to side effects than in the azithromycin groups (n = 7 and 11, respectively, for the 3- and 6-day courses).
The comparable effectiveness of three-day courses of azithromycin with standard courses of treatment with amoxicillin/clavulanate was confirmed in three more clinical studies, and in two of them the effect of azithromycin developed faster than the effect of the comparison drug. The results of a domestic randomized clinical and pharmacoeconomic study showed that a three-day course of azithromycin provides cure for acute sinusitis in a shorter period of time than a ten-day course of amoxicillin/clavulanate, more effectively prevents relapses of the disease, is better tolerated, is characterized by fewer adverse reactions than the comparison drug, and is more profitable from an economic point of view [54].
Controlled studies have demonstrated the high clinical and bacteriological effectiveness of azithromycin for tonsillopharyngitis in adults and children. It has been shown that azithromycin is not inferior in clinical effectiveness to phenoxymethylpenicillin and erythromycin. There is evidence of faster relief of symptoms of the disease in patients receiving three- and five-day courses of azithromycin, compared with patients receiving a standard course of phenoxymethylpenicillin and roxithromycin [55, 56]. At the same time, some studies have revealed a lower bacteriological effectiveness of azithromycin compared to phenoxymethylpenicillin [57–59] and a higher rate of disease relapses in the long term in patients treated with azithromycin [60, 61]. This may be due to the insufficient dose of azithromycin used in these studies.
A meta-analysis of controlled clinical trials showed that the effectiveness of azithromycin for tonsillopharyngitis largely depends on the dose and treatment regimen [58]. In children, the course dose of the drug should be 60 mg/kg (3 days at 20 mg/kg or 5 days at 12 mg/kg). According to the results of the meta-analysis, at this course dose, azithromycin was significantly (p < 0.00001) superior in effectiveness to 10-day courses of treatment with comparison antibiotics. Moreover, bacteriological failure in children receiving azithromycin at a course dose of 60 mg/kg was observed five times less often than when using ten-day courses of comparison antibiotics. On the contrary, at a course dose of 30 mg/kg, azithromycin was inferior (p = 0.02) in effectiveness in pediatrics to standard courses of comparison antibiotics. In children, three-day treatment regimens were less effective than five-day ones. In contrast, in adult patients, three-day treatment regimens were superior to five-day regimens. When using three-day treatment regimens (500 mg/day) in adults, there was a trend towards higher efficacy of azithromycin compared with ten-day courses of comparison antibiotics (p = 0.14).
The only clinical study used a single dose of azithromycin (30 mg/kg) in patients with tonsillitis, which was not inferior in effectiveness to a ten-day course of treatment with a comparator antibiotic [62], but the question of the possibility of using a single dose of azithromycin for the treatment of acute tonsillopharyngitis requires further study.
Azithromycin has proven to be an effective treatment for acute otitis media. It has been shown to be effective in three- and five-day courses in clinical studies, and in 2003 it was approved by the FDA for the treatment of acute otitis media in children in a single dose.
The effectiveness and safety of a single dose of azithromycin (30 mg/kg) have been studied in a fairly large number of clinical studies in children with uncomplicated acute otitis media. The summarized results of four studies indicate that, in general, the clinical effectiveness of a single dose of azithromycin in children with acute otitis is 84%, including for infections caused by Streptococcus pneumoniae - 91%, Haemophilus influenzae - 77%, Moraxella catarrhalis - 100 %, Streptococcus pyogenes – 64%, mixed infection of S. pneumoniae and H. influenzae – 25% [63]. The drug was very well tolerated: side effects were rare and mainly manifested as mild transient gastrointestinal disorders. In the two largest studies, the incidence of side effects with azithromycin was lower than that of the comparator antibiotics amoxicillin and amoxicillin/clavulanate.
According to the results of a meta-analysis, the frequency of failure when using short (less than five days) courses of azithromycin and 7-10-day courses of amoxicillin does not differ [64]. At the same time, azithromycin is significantly less likely (19%; p < 0.05) to cause side effects than amoxicillin.
Thus, azithromycin meets almost all the requirements for “ideal” drugs for the treatment of infections of the upper respiratory tract and ENT organs:
· exhibits high activity against the main pathogens of infections in a given localization, including “atypical” pathogens, the etiological role of which has recently been increasing;
· has favorable pharmacokinetic properties, allowing one to achieve high concentrations of the antibiotic at the site of infection and apply it once a day in short courses;
· has proven efficacy and safety in adequate clinical studies and is well tolerated by patients;
· thanks to the convenient treatment regimen and good tolerability, it allows for high patient adherence to treatment;
· is associated with low levels of resistance in major pathogens and may “overcome” low levels of resistance due to unique pharmacokinetic properties.
Azithromycin in the treatment of lower respiratory tract infections
The first of the macrolides, erythromycin, was created in 1952, but drugs of this series were rarely used until the dramatic outbreak of Legionella pneumonia (80s of the twentieth century), accompanied by a 30% mortality rate. It was quickly established that macrolides are the optimal drugs for the treatment of infections caused by intracellular infectious agents (legionella, mycoplasma, chlamydia), and this led to the widespread use of this group of antibiotics. A number of new drugs for oral and parenteral use have been created, differing in terms of pharmacokinetics and pharmacodynamics. The basis of the chemical structure of macrolides [1,5] is the macrocyclic lactone ring. Depending on the number of carbon atoms in the lactone ring, 14-membered (erythromycin, clarithromycin, roxithromycin), 15-membered (azithromycin) and 16-membered (josamycin, midecamycin, spiramycin) macrolides are distinguished. Azithromycin belongs to the azalide subclass because one carbon atom in its ring is replaced by a nitrogen atom. The structural features of individual drugs determine differences in pharmacokinetic characteristics, tolerability, the possibility of drug interactions, as well as some features of antimicrobial activity. Azithromycin is characterized by unique cellular kinetics, rapid and intense penetration into cells and interstitial tissues, high levels of distribution of the antibiotic in tissues and relatively low levels in the blood. Azithromycin well suppresses (Table 1) gram-positive (pneumococci, streptococci, staphylococci) and gram-negative (moraxella, Haemophilus influenzae) microorganisms and intracellular agents (chlamydia, mycoplasma, legionella, ureaplasma). Other macrolides (except clarithromycin) are less active against Haemophilus influenzae [5,6]. Considering that in the etiological structure of community-acquired pneumonia, the leading positions are occupied by pneumococci, Haemophilus influenzae, mycoplasma, chlamydia, and exacerbations of chronic bronchitis (chronic obstructive pulmonary disease), as a rule, are caused by pneumococci, Haemophilus influenzae, moraxella (less often - mycoplasma and chlamydia), It is becoming clear that azithromycin is often the antibiotic of choice for treating pulmonary patients. In Western and Southern Europe, the widespread use of macrolides has led to an increase (up to 30%) in pneumococcal resistance to them. The corresponding resistance rates in our country [1], according to various estimates, do not exceed 4–8%. The characteristics of azithromycin are determined not only by the spectrum of action, but also by the creation of high concentrations in the pulmonary parenchyma and alveolar macrophages. A comparison of the concentrations created in various biological media shows that the concentrations of azithromycin in the lung parenchyma are 8–10 times, and in alveolar macrophages 800 times higher than in blood serum. Thus, this drug should be highly effective in the treatment of pulmonary pathology. Azithromycin remains at the site of infection for 4–5 days or more, depending on the dose and tissue structure. Due to the release of the antibiotic from phagocytes during their destruction, the concentration at the site of infection quickly increases [1,5]. High intracellular penetration and accumulation in cells and infected tissues determines the effectiveness of azithromycin, which exceeds the effect of other antibiotics, in infections caused by intracellular pathogens, including pathogens of dangerous infectious diseases (brucellosis, tularemia, etc.). A feature of the pharmacodynamics of macrolides is a long-term post-antibiotic effect, due to which, when the antibiotic is used in minimal inhibitory concentrations, the effect of the antibiotic continues after its withdrawal. For azithromycin, a post-antibiotic effect lasting up to 90 hours is considered proven, and this makes it possible to reduce the duration of antibacterial treatment. Allergic sensitization to macrolides is relatively rare. Among the side effects, gastrointestinal manifestations predominate and, perhaps, some of them are due to the ability of macrolides to enhance intestinal motility. Side effects are more common when using erythromycin. Toxic and allergic side effects when using azithromycin are rare [1,4,5]. Azithromycin is approved for medical use in our country in several dosage forms: capsules 0.25 g, tablets 0.5 g, powder for suspension 2.0 g, powder for injection 0.5 g. Thus, the antibiotic can be used orally, intravenously and in step therapy mode. The drug has a convenient dosage regimen (administered once a day). Given the long-term post-antibiotic effect of azithromycin, this antibiotic was (and is) often used in short 3-5 day courses. The dosage form is a powder for the preparation of a suspension (2.0 g of azithromycin) which involves treatment with a single dose of an antibiotic. Features of pharmacokinetics allow the use of azithromycin once a day. Naturally, drugs used once or twice a day have greater compliance and are readily used by patients. There are various regimens for oral administration of azithromycin. The most common dosage for the treatment of pulmonary diseases is 500 mg on the first day of treatment and 250 mg every 24 hours for the next 4 days. With this regimen, the duration of treatment for pneumonia is 5 days. The treatment period for pneumonia caused by common bacterial agents (pneumococci, streptococci, Haemophilus influenzae, etc.) can be reduced to three days if the daily dose is 500 mg. The duration of treatment for pneumonia caused by mycoplasma and chlamydia is 14 days, and legionella pneumonia is 21 days. Our own experience of using azithromycin for 15 years is based on the treatment of more than 1,500 patients with pneumonia with this antibiotic, and all described oral therapy regimens, step-down therapy, and treatment with azithromycin in combination with b-lactam antibiotics were used with high efficiency. According to the Department of Pulmonology of the Central Clinical Hospital in 1984, macrolides (only erythromycin was used) accounted for only 9% of the structure of antibiotics used. In 2004, the frequency of their use tripled (27.3%), second only to b-lactam antibiotics. Five oral medications were used, of which azithromycin was the most commonly used (80%). The significant frequency of prescription of macrolides is explained by the rise in the incidence of chlamydial and mycoplasma infections, as well as the widespread use of combinations of macrolides with b-lactam antibiotics when the etiological deciphering is impossible. According to microbiological studies of sputum, pneumococcus still dominates as the leading etiological agent of respiratory infections (52.1%). In addition to pneumococcus, cultures of viridans streptococcus and Haemophilus influenzae were isolated from sputum. Gram-negative microorganisms and staphylococci were rarely detected. In recent years, the frequency of mycoplasma and chlamydial infections has increased significantly, and intracellular agents are often the cause of epidemic outbreaks in families and groups. Indications for the use of azithromycin are [1,5] upper respiratory tract infections (tonsillopharyngitis, acute otitis media, sinusitis), as well as bronchitis and community-acquired pneumonia. The so-called atypical pneumonias [2–5] are caused by intracellular agents—viruses, mycoplasma (50% of all cases), chlamydia, and legionella. Azithromycin is the best antibiotic to treat most of them. Brief differences between atypical pneumonias [6] are given in Table 2. The infection is often transmitted from person to person (in recent years, several family and work-related outbreaks of mycoplasma and chlamydial pneumonia have been observed). Etiological diagnosis is possible by identifying specific IgM antibodies in the blood serum or seroconversion (when studying paired sera). A study of the clinical manifestations of mycoplasma pneumonia has shown that a prodromal period in the form of malaise and respiratory syndrome, manifested by nasopharyngitis, tracheobronchitis [2,3,6], and less commonly otitis, is characteristic. The development of pneumonia is rapid, sometimes gradual with the appearance of fever or low-grade fever [2,6]. Chills and shortness of breath are not typical. Cough, often nonproductive or producing mucous sputum, is the dominant symptom. In 30–50% of patients, a paroxysmal, nonproductive, painful, whooping cough of low timbre is typical, sometimes accompanied by difficulty in inhaling [3]. These paroxysms of cough are often caused by the development of the phenomenon of tracheo-bronchial dyskinesia, in which the mobility of the pars membranacea of the trachea and large bronchi increases significantly. On auscultation, dry and/or local moist rales are heard. There is no crepitus or signs of compaction of the lung tissue. Pleural effusion rarely develops. Extrapulmonary symptoms are common: myalgia (usually pain in the muscles of the back and thighs), profuse sweating, muscle weakness, arthralgia, lesions of the skin and mucous membranes, gastrointestinal disorders, headaches, and sometimes insomnia. X-ray examination reveals typical pneumonic infiltration of the pulmonary parenchyma (usually focal and multifocal in nature), however, in 20–25% of patients only interstitial changes are detected, and occasionally no pathology is noted on standard radiographs (especially those performed in hard mode). Therefore, in cases where clinical pneumonia is beyond doubt, and the results of radiography are not conclusive, computed x-ray tomography can be used, which provides confirmation of the diagnosis due to viewing the image in various modes and the absence of hidden zones for the method. The phenomenon of tracheo-bronchial dyskinesia is detected when performing forced expiratory pulmonary tests. Characteristic is the appearance of additional “steps” on the spirographic curve. More accurately, the presence of this syndrome can be proven by fluoroscopy of the trachea with a cough test. The leukocyte formula of peripheral blood is usually not changed. Slight leukocytosis or leukopenia is possible. Occasionally, unmotivated anemia is noted. Blood cultures are sterile, and sputum cultures are uninformative. Mycoplasma pneumonia is characterized by dissociation of some clinical signs: high fever in combination with a normal leukocyte count and mucous sputum; low-grade fever with heavy sweats and severe asthenia. Thus, mycoplasma pneumonia has certain clinical features, the comparison of which with the epidemiological situation allows one to make the right decision on the choice of antibacterial drug. With chlamydial infection [3,6], the development of pneumonia is often preceded by a respiratory syndrome in the form of malaise and pharyngitis, occurring with a dry cough at normal or subfebrile body temperature. The development of pneumonia is subacute with the appearance of chills and fever. The cough quickly becomes productive with the release of purulent sputum. During auscultation, crepitus is heard in the early stages; local moist rales are a more stable sign. In lobar pneumonia, shortening of percussion sound, bronchial breathing, and increased bronchophony are determined. Chlamydial pneumonia can be complicated by pleurisy, which is manifested by characteristic pleural pain and pleural friction noise. With pleural effusion, dullness is determined by percussion, and when auscultated, a sharp weakening of breathing is detected. Some patients tolerate high fever relatively easily. A whooping cough-like course of chlamydial pneumonia has been described in children, which is associated with the frequent development of tracheobronchial dyskinesia, which is also a characteristic symptom of pulmonary chlamydia in adults. Of the extrapulmonary manifestations, sinusitis is more common (5%), and myocarditis and endocarditis are much less common. Radiographic findings are extremely variable. Infiltrative changes in the volume of one or more lobes are detected; often the infiltration is interstitial in nature. In typical cases, the leukocyte formula is not changed, but leukocytosis with a neutrophilic shift is often observed. Patient X., 15 years old, was hospitalized in the pulmonology department on the 7th day of illness. There is an outbreak of acute respiratory infection at school. In the class, 5 out of 25 students were diagnosed with pneumonia. The patient was diagnosed with pneumonia on the 2nd day of illness. Therapy with amoxicillin/clavulanate 2.0 g/day was started. Treatment for 5 days without effect. Fever persisted all days up to 38–38.5°C. On admission the condition was of moderate severity. Body temperature 38.5°C. Clinical and radiological findings are consistent with right lower lobe pneumonia. The blood test showed moderate leukocytosis without a neutrophilic shift in the leukocyte formula. Oral azithromycin 500 mg/day was prescribed. A few hours after the first dose of the antibiotic, the body temperature returned to normal. During examination, high titers of antibodies to chlamydia of the IgM class were found in the blood serum. Azithromycin was used for 12 days. The outcome is recovery. In this clinical observation, the basis for correct clinical assessment and selection of an effective antibiotic (azithromycin) was the characteristic epidemiological history and the lack of effect from 5-day therapy with an enhanced b-lactam antibiotic at an effective dose. In addition to monotherapy with azithromycin, this antibiotic is often prescribed in combination with b-lactam drugs. If a patient is hospitalized for moderate or severe pneumonia, a de-escalation tactic is often practiced [1,3,5], which involves the use of a combination of antibiotics for initial therapy and usually this is a combination of a b-lactam drug (aminopenicillins, cephalosporins, carbapenems) with a macrolide, which is prescribed based on the possibility of legionella or chlamydial infection. Subsequently, after the diagnosis is clarified, one of the drugs is discontinued.
Several years ago, on the 4th day of illness, patient N., 42 years old, was hospitalized in our department. Upon admission, the condition was serious: body temperature 39.0°C, unstable hemodynamics, respiratory rate – 36 per minute. Clinically and radiologically – bilateral multilobar (infiltration of 3 lobes) pneumonia. Leukocytosis 22.0 with a band shift of 30%. Antibacterial therapy was prescribed: meropenem 4.0 g/day. intravenously in combination with azithromycin 500 mg/day. orally. Pressor amines and intravenous glucocorticosteroids were used, and oxygen therapy was used. Hemodynamic parameters were stabilized within 4 hours and further use of steroids and pressor amines was discontinued. Etiologically, pneumonia was deciphered as Legionella (antibodies to Legionella were detected in the blood serum at a titer of 1:1024). The duration of treatment with azithromycin is 18 days, meropenem is 4 days (the drug was discontinued after the diagnosis of legionellosis was established). Oxygen therapy was used for 7 days. The outcome is recovery. It can be reasonably assumed that the outcome of the disease in the observed patient would have been questionable if empirical antibacterial therapy had been carried out only with meropenem, and azithromycin had been prescribed only after the Legionella nature of the pneumonia had been established. This observation prompted us to carry out de-escalation antibacterial therapy (b-lactam antibiotic + macrolide) in almost half of the patients with pneumonia and in all cases of treatment of severe pneumonia. For severe pneumonia, antibiotics are used intravenously. When used intravenously, azithromycin is dosed at 500 mg every 24 hours. The costs of antibacterial therapy must be taken into account, which can be quite significant. In recent years, so-called step therapy has been successfully used [1,3–5]. When using azithromycin using this method, treatment begins with intravenous antibiotic use of 500 mg every 24 hours. Upon achieving a clinical effect (usually after 2-3 days), when antibacterial therapy has provided an improvement in the patient’s condition, accompanied by a decrease or normalization of body temperature, a decrease in leukocytosis, it is possible to switch to oral administration of azithromycin (if good absorption is expected) at 0.25–0. 5/24 hours. While this technique is highly effective, it is less expensive not only due to the difference in prices for parenteral and tablet drugs, but also due to the reduced consumption of syringes, droppers, and sterile solutions. This therapy is easier to tolerate by patients and is less likely to be accompanied by side effects. Intravenous and stepwise administration of azithromycin is usually used in the treatment of severe pneumonia. When treating other bronchopulmonary infections, as a rule, you can limit yourself to oral therapy. The data presented and our own long-term experience indicate that azithromycin currently occupies one of the main positions in the treatment of bronchopulmonary infections.
Literature 1. Practical guide to anti-infective chemotherapy (Ed. L.S. Strachunsky, Yu.B. Belousov, S.N. Kozlov) // Smolensk, MAKMAH, 2007. – 464 p. 2. Nonikov V.E. Atypical pneumonia: the rebirth of macrolides // New Medical Journal. – 1995. – No. 1. – pp. 5–7 3. Nonikov V.E. Tactics of antibacterial chemotherapy of pneumonia //RMZh.–1997.–Vol. 5.–No. 24,– p.1568–1578 4. Nonikov V.E. Antibiotics-macrolides in pulmonary practice // Atmosphere: pulmonology and allergology. – 2004. – No. 2 (13). – pp. 24–26 5. Bartlett J. Pocket Book of Infectious Diseases Therapy // Lippincott Williams & Wilkins. – 2005 –6.– 349p. 6. Zackom H. Pulmonary Differential Diagnosis //WBSaunders.– 2000.– 885 p
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