Macrolides: drugs of choice or alternative for the treatment of pneumococcal infections

Following the introduction of technologies for the synthesis and industrial production of penicillin in the 40s., Began the "golden era" in the development of chemotherapy, accompanied by the discovery and development of new classes and groups of antimicrobial agents.

Their widespread use, along with improved sanitation and hygiene conditions, the widespread introduction of immunization resulted in a significant reduction in mortality from infectious diseases. However, these achievements are now under serious threat due to the emergence and spread of antibiotic-resistant bacteria, a considerable role in this belongs to pneumococci.

At the present time is the proven role of S. pneumoniae in the etiology of various diseases. From a clinical point of view, distinguish invasive and noninvasive infections. The former include diseases in which the pathogen was isolated from sterile normal loci (eg, cerebrospinal fluid, blood, etc.). For non-invasive infections, respectively, are local lesions (eg, otitis media, sinusitis, chronic bronchitis in the acute stage, etc.) [1].

S. pneumoniae is a major causative agents of community-acquired respiratory tract infections (pneumonia, acute exacerbations of chronic bronchitis, acute otitis media and sinusitis). According to official statistics in Russia every year about 400 000 cases of pneumonia, although the estimated number of over 1.5 million, with the pneumococcus is the major causative agent of community-acquired pneumonia (60%) [4]. In the etiology of acute otitis media also have a major role pneumococcus [5]. In addition to these diseases can cause pneumococcal meningitis, bacteremia, primary peritonitis. Pneumococcal meningitis is a leader in the structure of bacterial meningitis nemeningokokkovoy etiology [12].

Celebrated in many countries the growth of antibiotic resistance in S. pneumoniae affects the choice of drugs for empirical therapy. To optimize the empirical treatment of pneumococcal infections requires credible, regional and local data on antimicrobial antimicrobial agent. These data can be obtained by monitoring the resistance of clinical strains of S. pneumoniae. Pneumococcus is considered a "fastidious" microorganisms, so the study of its sensitivity is time consuming and expensive process that requires special culture media and reagents [13].

Penicillin-resistant pneumococci are found in all parts of the world (Fig. 1), but their frequency varies considerably. In the 1980s, has been defined mechanism of resistance to penicillin and other ъ-lactam antibiotics, which is to change the target of this class of antibiotics - penitsillinsvyazyvayuschih proteins (PRP). JLS are enzymes that catalyze the synthesis of important stages of peptidoglycan. The result of the interaction of ъ-lactams with the PSB is the formation of covalently bound through the active serine center of the complex. Changes PSB lead to a reduction of binding of this class of antibiotics, resulting in the need for their higher concentrations to inhibit the activity of DPM [1].

In the 1990s, from many countries began to receive reports of the increasing frequency of pneumococci пенициллинонечувствительных, and to date this problem has become global.

There are many programs of surveillance for antimicrobial resistance of pneumococci (SENTRY, PROTEKT, TRUST, CROSS, BASKETT, etc.), but to obtain comparable data of the problem is the priority use of data from a single project, conducted since the early 90s. - Alexander project [6,7,8,11].

Given the data of this project is possible to highlight the most "problematic" in terms of prevalence пенициллинонечувствительности regions / countries, which are:

● Asia - Hong Kong, Japan, Singapore, Korea, Thailand, Taiwan;
● Europe - Spain, Hungary, France, Portugal, Romania, Bulgaria, Turkey;
● Africa - South Africa;
● North and South America - Mexico, United States (South-Eastern states and Alaska), Brazil.

The most favorable situation is in Germany, Italy, UK, Netherlands and Canada.
Besides resistance to penicillin in recent years an increasing problem becomes resistant pneumococci to macrolide antibiotics (Fig. 2), chloramphenicol, tetracycline and co-trimoxazole [6,7,9,10,11].
Resistance to macrolides, particularly erythromycin, was very rare in the late 1970s and early 80s. However, in the late '80s. years. Research in South Africa have shown a high frequency eritromitsinorezistentnyh strains in combination with MDR pneumococci isolated from healthy children.

On the basis of Fig. 2 data, the following groups of countries on the frequency of occurrence of pneumococci makrolidorezistentnyh:

● countries with relatively low frequency of resistance - Brazil, Germany, Great Britain, Switzerland;
● countries with moderately high frequency of resistance - Mexico, South Africa, Belgium;
● countries with very high frequency of resistance - the U.S., Singapore, France, Japan, Hong Kong.

Great clinical importance is the knowledge of the mechanisms of resistance to macrolide antibiotics. There are three main mechanisms of resistance to macrolides and lincosamides:

1) the change of the target by methylation or mutation, which results in inability to bind the antibiotic to the ribosome;
2) active release (efflux), an antibiotic from the bacterial cells;
3) enzymatic inactivation of the antibiotic.

In 1956. resistance to erythromycin, the mechanism of which was associated with methylation of the ribosomal target of antibiotics, which ultimately led to cross-resistance to macrolides, lincosamides and streptogramins B (MLSV phenotype), was first described in staphylococci. Later it was found that this mechanism is encoded by a group of genes called erm (erythromycin ribosome methylase), which are found in many organisms, including pneumococci. In pneumococcal resistance to macrolides, lincosamides and streptogramins encoded by the genes erm B or, more rarely, erm A similar phenotype characterized by high levels of cross-resistance to macrolides and lincosamides. From a clinical point of view, 14 -, 15 -, 16-membered macrolides, lincosamides and will be ineffective in the treatment of infections caused by any such strains [10].

The mechanism of active release (efflux), encoded by the genes mef E and mef A, has been described in clinical strains of pneumococcus in 1997. An important feature of the mechanism of active release is that it causes resistance to 14 - and 15-membered macrolides while maintaining sensitivity to 16 - membered, lincosamides and streptogramins B (M-phenotype).

Also, be aware that one strain may be present and the gene mef, and gene erm, which leads to MLSV type of resistance.

Keep in mind that there are significant differences between countries and in the incidence of resistance mechanisms to macrolides. For example, in U.S. efflux mechanism occurs in 70% of pneumococci makrolidorezistentnyh compared with 6% in Italy. At the same time, the methylation of ribosomal and efflux occur with equal frequency in many Asian countries [11].

Thus, pneumococci possess unique abilities develop resistance to various classes of antimicrobial agents, as evidenced by contemporary epidemiological data. Significant geographic differences in prevalence levels and mechanisms to reduce the sensitivity dictate a need for studies of this phenomenon at the national, regional and local level in each country. It is based on these data we can develop recommendations for empirical treatment of pneumococcal infections in each region.

Monitoring antibiotkorezistentnosti pneumococci in the Russian Federation carried out since 1999. Institute of Antimicrobial Chemotherapy and the Scientific-methodical center of Russian Ministry of Health to monitor antibiotic resistance (Smolensk) and is part of a multicenter study of a Pegasus-Pegasus-2 (1999-2005)..

The aim of this study was to examine the level, structure, and phenotypes of resistance to antimicrobial agents in various regions of Russia, as well as their assessment of the dynamics in the period from 1999 to 2005. [1,2,13]

Phase "A" Project Pegasus-1 was carried out in 1999 and 2000. to include 15 centers of the Central, Volga, Southern, Ural and Siberian Federal Districts. According to this study (Fig. 3), moderately resistant to penicillin strains of S. pneumoniae accounted for 7%, while 2% of strains were penicillin MIC ≥ 2 mg / liter. All strains with intermediate resistance to penicillin remained sensitive to cephalosporins. The frequency of resistance to erythromycin was 6.2%. The most significant problem is the stability of S. pneumoniae to tetracycline (27.1%) and to co-trimoxazole (32.4%).

In phase "B" (2001 to 2002.) Attended by 25 centers in Central, Northwestern, Volga, Southern, Ural, Siberian and Far Eastern Federal Districts.

It is established that at the present time in Russia and, obviously, in Belarus, all macrolides retain high activity against S. pneumoniae. In 1999 and 2003. insensitive to erythromycin was 8.2% of strains, to azithromycin - 8.1% to clarithromycin - 8%. A marked downward trend in these indicators in 2004-2005. the corresponding values ​​were 6.6%, 6.4% and 6.4% respectively, but the differences between the two periods were not statistically significant [1,2,13].

As a result of a Russian research recommendations for empirical treatment of pneumococcal infections presumed etiology can be formulated as follows:

1) in the treatment of mild respiratory tract infections (community-acquired pneumonia, otitis media, sinusitis), oral therapy should be used. Drugs of choice are penicillins, including aminopenicillins (amoxicillin and amoxicillin / clavulanate), as well as 14 -, 15 - and 16-membered macrolides (azithromycin, clarithromycin, spiramycin). As an alternative, can be used - "respiratory" fluoroquinolones (levofloxacin, moxifloxacin), 2-3 generations of cephalosporins (cefuroxime, cefuroxime aksetil, cefotaxime, ceftriaxone), lincosamides (clindamycin).

2) in the treatment of severe infections often require parenteral therapy. As the choice of antibiotics can be used amoxicillin / clavulanate, cefotaxime, ceftriaxone, cefepime. Alternative drugs are 'respiratory' fluoroquinolones (moxifloxacin, levofloxacin), and carbapenems.

3) in the treatment of invasive infections (eg, meningitis), the drugs of choice are 3-4 generations cephalosporins (cefotaxime, ceftriaxone, or cefepime), and may be an alternative to vancomycin in combination with rifampicin or chloramphenicol.

Given the relatively high frequency of non-susceptible strains, we should limit the use of co-trimoxazole and tetracycline.

To date, azithromycin is the most commonly prescribed macrolide because of its unique pharmacokinetic and pharmacodynamic properties, which allows him for over 10 years to be one of the most popular macrolide antibiotics in different types of infectious diseases.

Azithromycin is the first of the 15-membered macrolide antibiotics, which form a subclass of azalides. It has the following advantages over erythromycin: a better effect on gram flora, especially Haemophilus influenzae, is not destroyed in the acidic environment, creates a much higher and more stable concentrations in the tissues, has a long half-life that allows him to take one twice a day and is used short course - 3 or 5 days, and acute urogenital chlamydiosis - one time, less likely to cause adverse reactions and drug interactions, acting on M. avium.

Azithromycin exhibits postantibiotichesky effect against microorganisms such as pyogenic streptococci, pneumococci, Haemophilus influenzae, Legionella. Moreover, the duration of postantibioticheskogo effect in Haemophilus influenzae and Legionella it is superior to clarithromycin [16,17].

According to many studies, macrolides, particularly azithromycin, have anti-inflammatory, immunomodulatory and mukoreguliruyuschim action. These properties of macrolides are related to their modulatory effect on phagocytosis, chemotaxis, Killing neutrophil apoptosis [18,19].

Adverse reactions in the application of azithromycin is rare. As a rule, they appear moderate reactions of the gastrointestinal tract as pain, nausea, diarrhea, and in most cases do not require discontinuation of the drug. According to several controlled studies, the frequency of diarrheal illness in the appointment of azithromycin is 6-9% [20,21,22]. Features pharmacokinetics can take it once a day, which provides high komplaentnost treatment.

The high effectiveness of azithromycin for infections of the upper and lower respiratory tract, such as tonzillofaringit, acute otitis media, sinusitis, bronchitis and community-acquired pneumonia, proven by many controlled studies, and found no significant differences when comparing the clinical and bacteriological effectiveness of azithromycin, appointed 3 and less - 5-day course, with other macrolides, oral penicillins and cephalosporins, prolonged use of data in which the infection is 7-10 days [23-31].

The use of azithromycin in infections of lower respiratory tract based on its ability to create long-term maintenance and high concentrations in bronchial secretions, bronchial mucosa, lung tissue and fluid lining the epithelium of the alveoli. As is known, azithromycin has good activity against both classical (S. pneumoniae, H. influenzae, M. catarrhallis), and "atypical" respiratory pathogens (S. pnemoniae, M. pnemoniae, Legionella spp.).

Macrolides (azithromycin and clarithromycin) are the drugs of choice for treatment of community-acquired pneumonia in patients aged 60 years who have no comorbidities and / or risk factors [32]. In hospitalized patients with moderate and severe community-acquired pneumonia, the addition of macrolides to beta-lactam therapy within the first 24 hours after admission, significantly improves the prognosis of the disease [33].

Gram-positive pathogens resistance problem to azithromycin in Belarus is not yet up to date.

A study was conducted clinical efficacy of azithromycin ("Azikar 'production company╚ Pharmacare Int. Co. ╩) Infections of the upper and lower respiratory tract infections (RTIs) and mild to moderate severity in outpatient therapy. The study included 45 patients with suspected pneumococcal etiology of PID (acute tonzillofaringit, acute bacterial rhinosinusitis, acute otitis media, infectious exacerbation of chronic obstructive pulmonary disease). Patients were randomized into two groups. The first group (25 persons) received Azikar 500 mg orally once daily for 3 days. The second group (20 persons) received 500 mg of amoxicillin three times daily for 7-10 days depending on the pathology. The study did not include patients with viral respiratory tract infections.

Clinical efficacy was assessed twice - at the end of therapy and two weeks after therapy. Account of the full set of clinical symptoms of respiratory tract infection (sore throat, swelling and redness of the posterior pharyngeal wall, pleural discharge, an increase of cervical lymph nodes, headache, productive cough, runny nose). A short course Azikara and a standard course of amoxicillin were virtually identical in clinical performance. Clinical efficacy of treatment (normalization of body temperature, leukocytosis, and the disappearance of subjective improvement) in both groups was similar and amounted, respectively, 88% and 85%. During treatment, patients taking Azikar, noted a more rapid disappearance of symptoms.

The data presented demonstrate the high efficiency of treatment of infections of the upper and lower respiratory tract pneumococcal etiology suspected drug 'Azikar "(azithromycin). No side effects and tolerability of drug confirm the available literature data on the high komplaentnosti therapy with azithromycin. Thus, to date, azithromycin, appointed by the short course, continues to be one of the most important drugs of modern antibiotic therapy as an outpatient and inpatient and the treatment of choice in the treatment of pneumococcal infections.

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