The use of clarithromycin in the treatment of chronic prostatitis

Such a high prevalence of CP is partly due to the fact that this diagnosis is the so-called "basket clinically ambiguous states." This is confirmed by the fact that over 90% of all cases of CP are abacterial prostatitis or chronic pelvic pain syndrome (CPPS) or category III prostatitis (according to the classification of the National Institute of Health, USA). The most accurate methods for diagnosing CP based on fields of biological material on selective culture media or cell culture. These methods are rather expensive and often used for scientific purposes. The diagnosis of bacterial prostatitis is performed by seeding 5% blood agar with the identification of the pathogen and determination of its sensitivity to antibiotics.

Regardless of how the introduction of the prostate gland in a variety of bacteria can cause clinically either the same or varied during the inflammatory process. According to W. Jadassohn et al. (1950), especially severe the prostate caused by mixed infection Staph. aureus and E. coli. E. coli, apparently, often falls into the prostate gland or lymphatic haematogenously from the intestine. There may be a urethral astsendiruyuschy path as well as downward urinogenous infection. Koliuretrit almost regularly complicated by prostatitis, and koliprostatit in turn flows to the natural posterior urethral lesion. According to EM Meares (1992), E. coli (together with E. feacalis and Staph. aureus) is a common cause of acute and chronic bacterial prostatitis.

O. Kostyukovsky and EA Smooth (1992) in the prostate gland secretions 48.7% of patients with chronic prostatitis identified nedifteriynye bacteria of the genus Corynebacterium. Important in this selection was the so-called mikrokorineform: Corynebact. pseudogenitalium - in 47,5%, Corynebact. genitalium - in 22.5% of cases. 37.5% of bacteria had mikrokorineformnyh biochemical properties relevant Corynebacterium group JK, which were first isolated in a separate group in 1976, their distinctive feature - high resistance to antibiotics. Suggest that multidrug-resistant strains are mutants of Corynebacterium skin flora, passed through the selective antibiotic selection. In addition to the prostate, they are the cause of septicemia, endocarditis, soft tissue and skin. Most infections caused by bacteria of JK, - this hospital infections in immunocompromised patients [Wichmann S. et al., 1985]. In prostatic secretions of patients with prostatitis mikrokorineformy were planted in 44.9% of cases.

Chronic prostatitis, caused by Actinomices israelii, is extremely rare [De Sauza E. et al., 1985]. However, his place in the overall structure of bacterial prostatitis can grow both through oral-genital contact (oropharyngeal and pulmonary actinomycosis develops as a result of the colonization of actinomycetes carious teeth and tonsillar crypts), and due to widespread use of intrauterine devices [Gremillion DG, Golbrayt M . 1988; Sykes GS, Shally G., 1981].

In the general drift of bacteria infections in the prostate gland is predominantly hematogenous route. We describe the acute and chronic prostatitis, caused by agents of typhoid fever, brucellosis, listeriosis, etc. Usually, when bacteriological examination of secretions of the prostate received transperineal puncture, ie under conditions excluding contamination of the urethral flora, pathogens urethral infections, sexually transmitted infections are not detected or isolated banal bacteria (staphylococci, streptococci, enterobacteria), relating to the normal inhabitants of the urinary tract and bowel, and often devoid of signs of pathogenicity. Interestingly, the presence of bacteria in secret, does not always correlate with objective signs of inflammation - increase the number of leukocytes in prostatic secretions [Kaplun, MI, 1984]. So often a diagnosis of chronic bacterial prostatitis, delivered on the basis of the selection of seed from the prostate gland eksprimata different bacteria, is not justified [Kahn D., 1984]. Very low efficiency of antibiotics in chronic prostatitis distinguishes this disease from other bacterial infections. Therefore, the usual approach to chronic prostatitis as a manifestation of infection is largely untenable and can not be satisfactorily explained. We believe that the first place is kanalikulyarny route of infection of the prostate. Probable and lymphogenous pathways for infection of the urethra through the anterior lymphatic plexus Panizza, anastomosing lymphatic vessels with cancer. VN Tkachuk et al. (1989) suggest that the occurrence of chronic prostatitis is associated with the transfer of hematogenous infection in the prostate gland due to uretrovenoznogo reflux, with a reflex hemodynamic disorders and motility in the gland due to irritation of seed products tubercle inflammation of the urethra, as well as uretroprostaticheskim reflux. However, the problem is to evaluate the response of a target organ for infiltrated urethral microorganisms [1].

Chlamydia in scrapings from the urethra are found about equally often as the persons who have been diagnosed with prostatitis for the first time after single or multiple migrated urethral infection and in patients who have disease of the prostate associated with hypothermia, angina, intestinal infections (41.6 and 36.8%, respectively). This explains why the WHO experts consider unproven or questionable relationship urethral infection with chronic prostatitis and why they do not refer it to the complications of gonorrheal or NGU [Report a WHO Scientific Group, 1984]. When infection of the prostate gland in the formation of protective immunity involves both antigen-specific and nonspecific factors common immune system and immune system of mucous membranes. The nature of the course and prognosis are determined by the activity of effector mechanisms of the immune system, such as in mycosis plays the decisive role of the phagocytic system and T-lymphocytes to the patient. Activation of these mechanisms of immune system cells, and is provided as waste products of pathogens, as well as a variety of endogenous immunoregulatory factors (chemoattractants, inflammatory mediators, proteins of the complement system, cytokines, antibodies, mediated by integrins and molecules of the MHC-I and MHC-II, etc.) [Kashkin KP, 1995].

Biological features of urethral pathogens, sexually transmitted infections, no significant effect on the incidence of chronic prostatitis, although clearly reflected in the frequency and clinical presentation of other urinary tract lesions and distant metastatic complications of urethritis. In addition, it is known that chronic prostatitis is often observed in isolation from urethral infection, and its frequency among men 40 - 50 years is 30 - 40% [Goryunov V., Kuzmin, 1988; Colleeu S., Mardh P. - A., 1984].

Due to the uncontrolled use of antibiotics, massive dosages, prolonged courses of treatment of microbial flora in patients with prostatitis began to change [2]. In crops began to appear more often secret gram-positive flora. Thus, MF Trapeznikov et al. (1995) for microbiological studies the secret of the prostate in 30 patients with chronic bacterial prostatitis have identified 49 species of microorganisms cultures 7 (their number is a secret cancer was greater than or equal to 104 CFU / ml), and in a monoculture is particularly common Staph. epidermidis (50% of patients), Str. faecalis (16,7%); 25% of patients were isolated Gram-negative enterobacteria. Associative microflora consists mainly of gram-positive cocci in two-component associations, and the most common association was Str. faecalis and Staph. epidermidis.

For the treatment of patients with CP are often a number of macrolide antibiotics [4]. They have a high therapeutic efficacy. One of the most well-known macrolide is clarithromycin (Klarikar production of "Farmakar"). The drug belongs to a semi-synthetic 14-membered macrolide, erythromycin A derivatives [5]. The presence of the methoxy group at position 6-lactone ring gives it a heightened kislotostabilnost and improved, compared with erythromycin, antibacterial and pharmacokinetic properties. Stability to hydrolysis by the action of clarithromycin hydrochloric acid is 100 times higher than that of erythromycin, however, the maximum antibacterial effect of the drug is in an alkaline medium [9]. The antimicrobial effect is due to a violation of protein synthesis by ribosomes of microbial cells. Clarithromycin is highly soluble in lipids, and therefore is widely distributed in organs, tissues and cells of the microorganism. The maximum concentration of drug in mononuclear leukocytes and polymorphic exceeds that in serum at 10-40. Clarithromycin does not create long subingibiruyuschih concentrations, and its absorption is independent of food intake.

Clarithromycin interacts with the host's immune system, unlike the vast majority of antibiotics, with an immunosuppressive effect, increases the phagocytic activity of macrophages and neyrofilov, and to a greater extent than erythromycin and dzhozamitsin. Revealed a synergistic bactericidal effect of clarithromycin in combination with serum complement [10]. In addition, in the presence of clarithromycin increases the activity of T-killers, which has a value in the treatment of bacterial infections, complicated by viral superinfection. Clarithromycin penetrates well into prostatic tissue and create a concentration sufficient for the treatment of chronic prostatitis [7]. Accumulating in immunocompetent cells, the antibiotic enhances their phagocytic function. Clarithromycin is approximately 78% metabolized in the liver by demethylation and hydroxylation, with the participation of cytochrome P450. In the body produces an active metabolite - 14-gidroksiklaritromitsin, which is not inferior to (and for a number of pathogens and superior) on the antimicrobial action of the main drug [3]. 14 gidroksiklaritromitsin partially formed already in the process of first-pass biotransformation of clarithromycin, so when ingested antibiotic concentration of 14 gidroksiklaritromitsina in plasma is higher than after intravenous administration [8]. In this regard, the effect of the first passage through the liver has almost no effect on the activity of the drug. From this point of view, and parenteral administration has little advantage over enteral. Thanks to the synergy of its active metabolite clarithromycin retains a high activity level even if the drug in the blood is slightly lower minimum inhibitory concentration. Metabolites other macrolides do not have the antibacterial activity [8].

When using high doses may saturate the enzyme systems and reducing the metabolism, which is accompanied by increased bioavailability of the antibiotic. Clarithromycin, a 14-membered macrolide increases the endogenous production of glucocorticoids, providing deksametazonopodobnoe action. This helps the rapid removal of edema. Klarikar rapidly absorbed from the gastrointestinal tract after oral administration. After receiving a single dose of 250 mg maximum plasma concentration observed after 2 hours. Equilibrium concentration in plasma is reached after 2-3 days and is approximately 1 mg / ml. Klarikar little bound to plasma proteins. [2]

Klarikar (clarithromycin) - one of the few antibiotics that have predictable metabolism. Thanks kislotostabilnosti when taking clarithromycin does not depend on the time of the meal. The place of absorption of the drug is the upper section of the small intestine, so the bacterial flora of the lumen of the lower intestine (saprophytes) remains unaffected [10]. There are no events dysbiosis. Clarithromycin is out of the body in two ways: through the kidneys and through the biliary system (the other macrolides have a pronounced hepatic excretion path). In general, renal function is more important for the elimination of clarithromycin, since it is excreted in the urine in combination with its active metabolite. This allows you to receive better clinical efficacy in the treatment of urethritis, prostatitis and other infectious and inflammatory diseases of the urinary system.

While taking the drug orally at a dose of 250 mg every 12 hours about 20% of the excreted in the urine unchanged and 10-15% - in the form of the active metabolite, when administered a dose of 500 mg over intervals similar proportion of unchanged antibiotic in the urine of 30% in maintaining the same amount of metabolite (10-15%). Excretion in the stool is 40% [7].

Improvement of antibiotic therapy is in the direction of creating new and better antibiotics, and on the way to develop new programs to use them. There is a new concept - postantibiotichesky effect. Some antibiotics (macrolides and fluoroquinolones modern) create extremely high concentrations and after discontinuation of its action continues. [6], which allows the use of short courses, one-or two-time reception during the day (Table I) and increases komplaentnost therapy.

Dosing regimens of some macrolides.

We examined 150 men (mean age 26.8 years) who suffered from urethritis of various etiologies (group 1) and 86 physically healthy men aged 19 - 29 years (mean age 25.6 years) without urethritis and other urological diseases in history, with no reports of dysuria, pain or sexual dysfunction (group 2). In group 1, chronic prostatitis was diagnosed in 44.1% of patients with chronic Trichomonas urethritis, at 59.5% - chronic abacterial urethritis current, at 55.6% - from chronic urethritis postgonoreynymi etc. These figures were comparable to those previously identified the frequency of chronic prostatitis: the 74.1% of patients with chronic negonoreyny and in 72.2% of patients with chronic gonorrheal urethritis. Our studies also confirm the high frequency of detection of objective and laboratory signs of chronic prostatitis in otherwise healthy men who are in the same climatic, household and industrial conditions.

In a study of healthy men of the 2nd group (86 people). Asymptomatic form of chronic prostatitis was found in 20.8% of cases. Established significant differences in the incidence of prostatitis in men aged 17 to 20 years (mean age 18.6 years) and from 21 to 29 years (mean age 24.7 years) respectively 13.8% and 35% ( p <0.01).

The survey identified two groups of men with chronic prostatitis clinic at the age of 18 to 49 of 20 people each. Indications for examination were complaints of pain in the perineum and inguinal region, mucous and pus from the urethra, dysuria (cramps, frequent urination). The first group we assigned patients with predominantly gram-positive flora, the second - with Gram.

As a means of antimicrobial therapy in group 1 used the drug Klarikar ("Farmakar") at a dose of 500 mg twice daily by mouth. Duration of antibiotic therapy was determined by the clinical form of the disease and the duration of infection and was on average 10 days. In the second group served as the base drug fluoroquinolone. Fluoroquinolone therapy and clarithromycin combined with drugs that improve the microcirculation (trental, chimes, Aescusan), with vitamin therapy (vitamin E, an antioxidant complex) and physiotherapy (LOD). All patients in the 1st, 10th and 15th day were performed ultrasonography of the prostate, a finger examination, Uroflowmetry. Prior to treatment seeding of the prostate secret on the flora and antibiotic sensitivity. Sowing was repeated after 10 days. In order to clarify the immune status was performed immunnogramma (Tx, T, T and B lymphocytes, null cells, load index) before treatment, on the 5th and at 7-10 days.

In all patients prior to treatment was an increase in size due to swelling of glands to 1,4 ╠ 0,3 cm, the maximum rate of urine flow (Qmax), according to Uroflowmetry, 12-16 ml / s with a minimum volume of 150 ml of urine. In crops saw an increase in gram-negative flora in 12 patients (30%) patients, gram-positive flora - in 12 (30%) in 8 patients (20%), Staphylococcus epidermidis sown in 6 (15%) microflora is not sown.

Отличительной особенностью иммунограммы при хроническом простатите являлся высокий уровень нулевых клеток (30-35) в начале обострения, что свидетельствует о запаздывающей дифференцировке лимфоцитов т.е. дефекте первой фазы иммунного ответа.

К 10-му дню от начала лечения в первой группе стойкое улучшение отметили 12 пациентов (60%), к 15 дню - 19 пациентов (95%). По данным УЗИ размеры предстательной железы нормализовались у всех 20 мужчин, максимальная скорость потока мочи (Qmax), по данным урофлоуметрии, увеличилась до 18-22 мл/с. Во второй группе стойкое улучшение к 10-му дню наблюдалось у 9 пациентов (45%), к 15 дню - 17 (85%). По данным УЗИ размеры простаты к концу лечения нормализовались у 17 (85%) мужчин. Максимальная скорость потока мочи (Qmax), по данным урофлоуметрии, увеличилась до 17-19 мл/с. Эрадикация микрофлоры достигнута у 88,6% больных обеих групп.

При исследовании иммунограммы у больных, принимавших кларикар, имело место снижение уровня нулевых клеток и повышение уровня Т-лимфоцитов уже к 5-м суткам от начала лечения. У пациентов второй группы дифференцировка лимфоцитов начиналась не ранее 7-го дня, а у 4 мужчин - только к 10-му дню, когда необходимость в Т-лимфоцитах снижается и нарастает потребность в В-лимфоцитах. Другими словами, больные хроническим простатитом нуждаются в стимуляции первой и модуляции второй фазы иммунного ответа, если с первого дня лечения они не начинают прием антибиотика с иммуномодулирующим действием (клариторомицин).

Таким образом, кларитромицин (╚ Кларикар ╩, Pharmacare) является адекватным антибактериальным препаратом для терапии хронических простатитов с предполагаемой или подтвержденной грамположительной флорой, обладающим высокой эффективностью и удовлетворительной переносимостью. Приём кларитромицина в суточной дозе 500 мг в течение 14 суток обеспечивает высокий клинико-микробиологический эффект.

Препарат хорошо проникает в ткань предстательной железы и создает в ней концентрации, достаточные для лечения хронического простатита.

Взаимодействуя с иммунной системой макроорганизма, повышая фагоцитарную активность нейрофилов и макрофагов и вызывая синергичный бактерицидный эффект при сочетании с комплементом сыворотки и стимуляцией активности Т-киллеров, кларитромицин позволяет не прибегать в комплексном лечении к иммуномодуляторам, что значительно снижает его стоимость.

Иммуномодулирующий эффект кларикара отмечен и у больных с грамотрицательной микрофлорой, что позволяет использовать его в комплексной терапии вялотекущих или резистентных форм хронического простатита даже при отсутствии бактериологического подтверждения чувствительности.
Обладая противоотечным действием, кларитромицин (кларикар) в большей степени, чем другие антибактериальные препараты, уменьшает отек простаты и способствует нормализации мочеиспускания.

References:

1. Панкратов В.Г. Инфекции передаваемые половым путем: эпидемиологические аспекты, врачебная тактика и принципы организации лечения больных. √ ╚Рецепт╩, - №5, - 2004, - 199-127.
2. Страчунский Л.С. Состояние антибиотикорезистентности в России // Клиническая фармакология и терапия. 2000. Number 2. С. 6-9.
3. Страчунский Л.С., Козлов С.Н. Макролиды в современной клинической практике. Смоленск, 2002. С. 245.
4. Тютюнник В.Л., Алиева С.А., Серов В.Н. Антибактериальная терапия заболеваний, передающихся половым путем, и лечение ее грибковых осложнений // Фарматека. 2003. № 11. С. 20-26.
5. Craft JC, Siepman N. Overview of the safety profile of clarithromycin suspension in pediatric patients. Pediatr. Infect. Dis. J., 1993, 12: 142-147.
6. Blondeau JM. The evolution and role of macrolides in infectious diseases. Expert Opin Pharmacother 2002;3:1131-51.
7. Kohno S., Koga H., Yamaguchi K., et al. A new macrolide, TE-031 (A-56268), in treatment of experimental Legionnairs' disease. J. Antimicrob. Chemother., 1989, 24: 397-405.
8. Rubinstein E. Comparative safety of the different macrolides. Int J Antimicrob Agents 2001; 18 (suppl. 1):71-6.
9. Scaglione F., Demartini G., Fraschini F. Distribution of clarithromycin to intracellular and extracellular sites of infection: an overview. In: New Macrolides, Azalides, and Streptogramins in Clinical Practice. Neu HC, Young LS, Zinner SH, Acar JF (Eds.). New York, etc., 1995: 380-385.
10. Yokota Т., Suzuki E., Arai К. TE-031 (A-56268), a new macrolide, its in vitro antibacterial activity, synergy of bactericidal effect with serum complement and mouse cultured macrophages, and incorporation into leucocytes. Chemotherapy, 1988, 36: 59-70.