Experience of using azithromycin in urological practice

In the IMMA medical centers, diagnostic measures, medication and alternative therapy are performed for any pathologies of the sexual and urinary sphere of various origins. Unnoticeable symptoms and an asymptomatic incubation period, traditionally characteristic of an infectious lesion, prove the importance of regular preventive examinations.

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Get a consultation with a urologist;
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Use the services of a pediatric urologist;
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Damage to the lining of the urinary canal, or urethritis, is common in both sexes. But it is more often detected and has more pronounced symptoms in men. The reason for this fact lies in the peculiarities of the physiological structure of the ureter. If in women it is short and quite wide, then in the male body it is a long and narrow canal that has a number of bends and changes in width.

In the female body, infectious agents are either immediately washed out of the urethra, without having time to gain a foothold and cause pathological changes, or they penetrate higher. The complex structure of the urethra in the male body determines the severe course of any inflammatory phenomena, accompanied by possible urination disorders.

Azithromycin: indications for use and contraindications

The manufacturer's instructions for the drug indicate the following pathologies for which the drug is sufficiently effective:

inflammatory processes in the respiratory tract, with the formation of sinusitis, tonsillitis, pharyngitis, laryngitis, otitis media, pneumonia or exacerbation of chronic bronchitis;
damage to the genitourinary tract without secondary complications - urethritis, cervicitis;
infection of the dermis and soft tissues - infectious superficial pyoderma, erysipelas, dermatitis;
initial borreliosis, scarlet fever, gastrointestinal pathologies associated with Helicobacter pylori.

The medication is not prescribed for complex diseases of the kidneys, liver, or allergic reactions to macrolides. The suspension is not used for babies weighing no more than 5 kg, and tablets and capsules - less than 45 kg.

Adverse reactions during therapy

Frequent clinical signs of the occurrence of a non-standard effect on treatment include:

problems with visual acuity;
attacks of vomiting with nausea;
discomfort in the abdominal area;
insufficient lymphocyte content;
disturbance of acid-base balance in the blood.

Almost 1% of patients experienced the following:

vaginal infections, oral candidiasis;
vestibular dysfunction, constant drowsiness;
convulsive syndrome, insufficient presence of leukocytes in the blood;
cephalgia, loss of sensitivity of receptors responsible for taste and smell;
constipation, digestive problems, active gas formation;
gastroduodenitis, rapid loss of strength;
vaginitis, dermatological rashes, obsessive itching.

Adverse reactions to Azithromycin in 0.1% of those undergoing treatment were:

increased neutrophil content, decreased platelet count;
anemia of hemolytic origin;
increased activity, unreasonable excitement;
anxiety, outbursts of aggression;
asthenic syndrome, tingling sensation, ants moving across the skin;
lethargy, neuroses, insomnia;
discoloration of the skin in a yellow tint, symptoms of hepatitis;
Quincke's edema, nettle fever, severe photosensitivity;
exudative erythema – polymorphic, malignant course;
anaphylactic shock, fungal infection.

Occasionally, an acceleration of the heart rate, ventricular arrhythmia, and pain in the chest space are recorded. Similar symptoms can be provoked by other macrolides. Antibiotics can cause a decrease in blood pressure and increase the QT interval.

Sometimes a decrease in hearing acuity, asthenic bulbar palsy, motor restlessness, liver dysfunction, hepatitis with necrotic complications are recorded. In most cases, adverse reactions occurred in patients taking Azithromycin in high dosages for a long period. Studies have shown that the resulting consequences are reversible.

Experience with the use of azithromycin in urological practice

Azithromycin is a representative of 15-membered macrolides. Like all macrolides, it has a bacteriostatic effect, disrupting the process of protein synthesis in target microorganisms by stopping the processes of translocation and transpeptidation [2]. However, under certain conditions, when creating higher intracellular concentrations, azithromycin can exhibit a bactericidal effect on some microorganisms. Azithromycin (Zitrocin and others) is active against a large number of gram-positive and gram-negative microorganisms, including intracellular pathogens. The greatest activity of azithromycin as a representative of the macrolide class was noted against gram-positive pathogens, in particular Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae (except for methicillin-resistant strains). Azithromycin is not active against enterococci (like all macrolides) [12,15]. With regard to gram-negative microorganisms, azithromycin has the highest activity among its class of drugs against Haemophilus influenzae, including strains that produce b-lactamases. It is moderately active against Salmonella spp., Shigella spp., Yersinia enterocolitica, Campylobacter jejuni, Helicobacter pylori [10]. The most important thing is that azithromycin exhibits high activity against “atypical” and intracellular pathogens, as well as STI pathogens. The drug acts on Legionella pneumophila, Mycoplasma pneumoniae, Mycoplasma hominis, Chlamydophila pneumoniae, C. trachomatis, Neisseria gonorrhoeae, Haemophilus ducreyi, Ureaplasma urealyticum, Treponema pallidum [15,19]. Recently, it has become known about the clinically proven activity of this drug against certain types of pathogens of malaria, toxoplasmosis, whooping cough, Lyme disease and the Mycobacterium avium complex [14]. In addition to the direct antibacterial effect, azithromycin, like all macrolides, has an effect on the nonspecific anti-infective defense system. The interaction of the antibiotic with phagocytes is of great clinical importance, as a result of which the activity of free radical oxidation and the release of anti-inflammatory cytokines are reduced, chemotaxis, phagocytosis and killing are activated. In addition, macrolides have membrane-stabilizing activity, improve mucociliary clearance and reduce mucus secretion. Azithromycin has the highest degree of penetration among macrolides into polymorphonuclear leukocytes and remains in them much longer, which greatly increases the ability for phagocytosis and anti-infective protection. The high anti-inflammatory, immunomodulatory and mucoregulatory effect of azithromycin has been proven by experimental and clinical studies [6]. One of the main mechanisms of immunomodulatory action is a change in the virulence factors of pathogens. Antibiotics that inhibit protein synthesis cause a change in the cell membrane, characterized by a decrease in the expression of proteins with antiphagocytic functions (M protein), which increases the fixation of the C3 component on the bacterial wall, reduces the need for opsonins and improves phagocytosis. On the other hand, phagocytes also influence the activity of antibacterial drugs. They secrete substances that have a bactericidal effect and increase cellular permeability. As a result, synergy with the drug is observed and the bactericidal effect of lysozyme, which destroys microorganisms even at low pH values, is enhanced[6]. Any chemotherapy drug has side effects when used. However, macrolides are rightfully among the safest antibacterial drugs. When taking azithromycin, cases of vaginitis and nephritis, headache, dizziness and drowsiness, adverse events from the gastrointestinal tract, increased fatigue, paresthesia, allergic manifestations in the form of angioedema, skin rash, and urticaria were recorded. In 64% of cases these phenomena were mild and in 30% moderate forms, and their frequency did not exceed 1%. There is no expected risk of fetal harm when using this drug in pregnant women and there is no evidence of fetal toxicity in animal studies [9]. Resistance of microorganisms to azithromycin is mainly (>90%) determined by two mechanisms: active removal of the drug from the microbial cell and modification of the target of its action, and the second mechanism usually gives a high level of resistance. In Russia, the problem of resistance to macrolides, and in particular to azithromycin, does not yet pose serious problems and amounts to only 5–6% (the dominant mechanism of resistance is the active release of the antibiotic from the microbial cell, much less often - methylation of ribosomes) [6]. Azithromycin (Zitrocin, etc.) has one of the highest tissue affinity among antibacterial drugs. The maximum accumulation of the drug, especially with the development of microbial inflammation, is observed, in addition to the lung tissue and mucous membrane, organs of the female reproductive system, gastrointestinal mucosa, also in the prostate gland and urethra. The concentration of azithromycin in monocytes, macrophages, fibroblasts and polymorphonuclear leukocytes is tens and hundreds of times higher than the serum concentration. The high tissue concentrations created, significantly exceeding the MIC of sensitive microorganisms, determine the pharmacodynamic advantages of macrolides. In addition, the accumulation of macrolides in the lysosomes of phagocytic cells forms, with the effective fusion of phagosomes and lysosomes, therapeutic concentrations in phagolysosomes and cytoplasm - the habitat of Chlamydia spp., Legionella spp., Mycoplasma spp., the role of which in the development of infections of the lower parts of the urogenital tract - urethritis and prostatitis – in recent years, much more than the role of typical bacteria: E. coli and other enterobacteria, staphylococcus, enterococcus [5]. It follows that at the present stage in urological practice, azithromycin is used mainly for the treatment of sexually transmitted diseases. One of the most problematic urogenital infections is chlamydia. The genitourinary area is affected by serotypes C. trachomatis DK. The danger of this infection is its low-symptomatic course, late diagnosis, which results in complications, the main of which in both women and men is infertility. Experts pay special attention to the treatment of chlamydia and its complicated forms. Currently, the greatest difficulty is presented by the so-called persistent forms of chlamydia, which, in all likelihood, stopped their development at the stage of elementary bodies for unknown reasons. A similar condition is often observed after treatment, when the clinical symptoms have passed, but, according to laboratory tests, chlamydia is still detected [1]. The difficulties of treating chlamydia and other STDs are associated not only with the biology of the pathogens, but also with the fact that not all antibacterial drugs penetrate well into the inflamed tissue and secretions of the prostate gland, which is explained by the barrier function of the prostatic epithelium, an increase in the pH of the secretions of the gland and local microcirculation disorders. The data obtained from clinical trials indicate that azithromycin is a drug with good tissue pharmacokinetics; it accumulates to a high degree in the tissue and secretion of the prostate gland and remains there for a long time. In addition, for antibacterial drugs, not only the level of the drug in the blood and tissues is important, but to a greater extent the ratio of tissue concentrations and MIC values (minimum inhibitory concentrations) for the infectious agent. It has been shown that the concentration of azithromycin in secretions and prostate tissue exceeds the MIC values for C. trachomatis, Ureapl. urealyticum, N. gonorrhoeae and 24 hours after oral administration, when the maximum level of the drug in the gland tissue is observed, and after 72 hours, when the concentration of the drug in the secretion and tissue becomes the same [5]. The data obtained allow us to conclude that, due to its unique tissue pharmacokinetics, azithromycin can be prescribed for urogenital STIs in short courses or with long intervals between doses (for chlamydial infection, this interval is 7 days) [8]. Thus, since 2000, there has been a method for treating complicated forms (prostatitis, total urethritis, epididymitis) of urogenital chlamydial infection with azithromycin, 1.0 g once on days 1–7–14 of treatment (3.0 g per course), so called pulse therapy. In these forms of diseases, in more than 90% of cases, along with chlamydia, patients are diagnosed with the presence of other microorganisms (U. urealyticum, M. genitalium, Trichom. vaginalis, N. gonorrhoeae). Observations show that with this treatment regimen, relapses even after two years are observed in only 1.2% of men and 2.5% of women [8]. This effect cannot be achieved using any of the currently known macrolides or tetracyclines used in the treatment of chlamydia. The proposed course of fractional therapy of 1.0 g with an interval of 1 week is able to “cover” from 6 to 8 life cycles of C. trachomatis (one cycle is 48–72 hours). Currently, treatment of various forms of complicated chlamydia using pulse therapy is carried out not only in Russia, but also abroad [18]. And in our country, this scheme was included in the “Federal Guide for Doctors” (formulary system), 2002. In especially severe cases of the disease, in addition to the oral form of azithromycin, the intravenous form is actively used. Clinical studies have shown that azithromycin is currently the drug of choice for the treatment of urogenital chlamydia in non-pregnant women and an alternative treatment for this disease during pregnancy. It also plays an important role in the prevention of pelvic inflammatory diseases. The inclusion of azithromycin in treatment regimens for inflammatory diseases of the pelvic organs seems promising in connection with the registration in Russia of the dosage form of the drug for intravenous administration. This drug is active against the main pathogens of the disease, ensures the rapid creation of a therapeutic concentration at the site of inflammation, and also has an immunomodulatory effect, increasing the nonspecific immunological reactivity of the body. The presence of azithromycin dosage forms for oral and parenteral administration allows the use of step-down therapy, which, in turn, helps reduce economic costs and improve the quality of life of patients during the treatment period [7]. Unfortunately, there are already the first reports indicating the emergence of isolated strains of chlamydia resistant to azithromycin [1]. This is a rather ominous sign, indicating the beginning of the process of chlamydia adapting to one of the main antibiotics of choice, which in the future is fraught with an increase in morbidity and new complications. Scientific research data were supported by data from clinical studies and then from the clinical use of azithromycin for gonococcal infections. They show that the activity of this drug against gonococci is quite high, and the number of strains resistant to this drug is no more than 3% (and, for example, to ciprofloxacin - about 35%) [3]. There is evidence indicating the possibility of using azithromycin for the treatment of early syphilis - in studies, this drug was slightly more effective than benzathine benzylpenicillin (97.7% versus 95%) during treatment, 3 and 6 months after completion of therapy [16]. Azithromycin has long been used to treat chancroid (infection caused by Haemophilus ducreyi) [17], nongonococcal urethritis [20] and granuloma inguinale (donovanosis caused by Calymmatobacterium granulomatis) [13]. At the moment, azithromycin (Zitrocin, etc.) continues to be a unique drug for a number of infectious diseases, especially for urogenital infections. The problem of resistance of both gram-positive and gram-negative clinical strains of the main pathogens to azithromycin in Russia is not yet relevant and does not require a quick solution. A good tolerability profile allows this drug to be used in a wide range of patients. In recent years, it has become possible to use azithromycin for step-down therapy, primarily for complicated inflammatory diseases of the pelvic organs, due to the advent of a form for intravenous use. Azithromycin is one of the few antibiotics that, due to its low toxicity and the absence of serious side effects, is approved for use in children from an early age, as well as during pregnancy. When prescribing azithromycin, insufficient attention is paid to its immunomodulatory properties, but, most likely, over time, these non-antibiotic properties will find their full clinical use. Summarizing all of the above, it is necessary to emphasize that azithromycin not only has not exhausted its practical potential, but also continues to remain one of the most important and promising drugs in modern antibacterial therapy both in outpatient and inpatient settings. And the creation of new generic drugs based on azithromycin that deepen its immunomodulatory properties opens up new broad horizons for its use, including in the field of urological practice. Literature 1. Akovbyan V.A. Rational therapy of sexually transmitted infections. Consilium medicum, 2000, v. 2, No. 4 2. Veseloye A.V., Kozlov R.S. Azithromycin: modern aspects of clinical use. Clinical microbiology and antimicrobial chemotherapy, 2006, vol. 8, No. 1 3. ARGON study, Research Institute of Agricultural Sciences, SGMA. 2002–2004. Preliminary data. 4. Karpov O.I. Original drugs and copies of macrolides: opposing trends. medi.ru Information for healthcare professionals. 2005. 5. Komarov R.V., Derevyanko I.I., Yakovlev S.V. and others. Pharmacokinetics of azithromycin in urogenital infections. Infections and antimicrobial therapy. 2001, Vol.Z, No. 6 6. Ushkalova E.A. The use of azithromycin for the prevention and treatment of inflammatory diseases of the pelvic organs and urogenital chlamydia. medi.ru Information for healthcare professionals. 2005 8. Chebotarev V.V., Chebotareva N.V., Kasymov B.M., Gomberg M.N. Long-term results of treatment of patients with complicated forms of urogenital chlamydia with azithromycin according to scheme 1–7–14. Original articles IPPPMz, 3, 2003 9. Data available from www.fda.dov. l0. Delmee M., Carpenter M., Glupczynski Y., et al. In vitro susceptibilities of 180 clinical isolates of Haemophilus influenzae to ampicillin, amoxicillin/clavulanat, cefaclor, cefuroxime, cefotaxime, clarithromycin and azithromycin. Acta Clin Belg 1996;51:237–43 11. Hoepelman IM, Schneider MME Intern J Antimicrob Agents 1955;5:145–67 12. Mendes SM, Sinto SI, Oplustil CP.,et al. In vitro susceptibility of gram–positive cocci isolated from skin and respiratory tract to azithromycin and twelve other antimicrobial agents. Braz J Infect Dis 2001;5:269–76 13. 0'Farrel N. Donovanosis. Sex Transm Infect 2002; 78:452–7 14. 0hrt C, Willingmyre GD, Lee P, et al. Assessment of azithromycin in combination with other antimalarial drugs against Plasmodium falciparum in vitro. Antimicrob Agents Chemother 2002;46:2518–24 15. 0mura S, editor. Macrolide Antibiotics. 2 edition. Academic Press; 2002. 16. Riedner D., Rusizoka M., Todd J., et al. Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis. N Engl J Med 2005;22:353:1236–44 17. Schmid GP Treatment of chancroid. Clin Infect Dis 1999;28 (Suppl l):S14–20 18. Shepard RM, Weidler DJ, Garg DC et al. Program and Abstracts of the 27th Interscience Conference on Antimicrobial Agents and Chemotherapy. New York, USA, Oct.4–7, 1987;abstr.239 19. Stout JE, Sens K., Mietzner S. Comparative activity of quinolones, macrolides and ketolides against Legionella species using in vitro broth dilution and intracellular susceptibility testing. Int J Antimicrob Agents 2005; 25:302–7 2O. Tan HH,Chan RK An open label comparative study of azithromycin and doxycycline in the treatment of non–gonococcal urethritis in males and Chlamydia trachomatis cervicitis in femal sex workers in an STD clinic in Singapore. Singapore Med J 1999;40:519–23