CLARITHROMYCIN instructions for use, description of the medicinal product CLARITHROMYCIN: contraindications, side effects, dosages, composition - tablets, coating. shell in the directory of medicinal

Description of the drug CLARITHROMYCIN

Clarithromycin inhibits the activity of the CYP3A4 isoenzyme, which leads to a slower rate of metabolism of astemizole when used simultaneously. As a result, there is an increase in the QT interval and an increased risk of developing ventricular arrhythmias.

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated due to the fact that these statins are largely metabolized by the CYP3A4 isoenzyme, and co-administration with clarithromycin increases their serum concentrations, which leads to an increased risk of developing myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients taking clarithromycin concomitantly with these drugs. If clarithromycin is necessary, lovastatin or simvastatin should be discontinued during therapy.

Clarithromycin should be used with caution in combination therapy with other statins. It is recommended to use statins that do not depend on the metabolism of CYP3A isoenzymes (for example, fluvastatin). If coadministration is necessary, it is recommended to take the lowest dose of statin. The development of signs and symptoms of myopathy should be monitored. When used simultaneously with atorvastatin, the concentration of atorvastatin in the blood plasma increases moderately and the risk of developing myopathy increases.

Drugs that are CYP3A inducers (for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) can induce the metabolism of clarithromycin, which can lead to subtherapeutic concentrations of clarithromycin and a decrease in its effectiveness. It is necessary to monitor the plasma concentration of the CYP3A inducer, which may increase due to the inhibition of CYP3A by clarithromycin.

When used together with rifabutin, the concentration of rifabutin in the blood plasma increases, the risk of developing uveitis increases, and the concentration of clarithromycin in the blood plasma decreases.

When used together with clarithromycin, plasma concentrations of phenytoin, carbamazepine, and valproic acid may increase.

Strong inducers of isoenzymes of the cytochrome P450 system, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentine, can accelerate the metabolism of clarithromycin and, thus, reduce the concentration of clarithromycin in plasma and weaken its therapeutic effect, and at the same time increase the concentration of 14-OH-clarithromycin - metabolite, which is also microbiologically active. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin differs against different bacteria, the therapeutic effect may be reduced when clarithromycin is used together with enzyme inducers.

The plasma concentration of clarithromycin decreases with the use of etravirine, while the concentration of the active metabolite 14-OH-clarithromycin increases. Because 14-OH-clarithromycin has low activity against MAC infections, overall activity against MAC infections may be affected, and alternative treatments should be considered for the treatment of MAC.

A pharmacokinetic study showed that co-administration of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours resulted in a marked suppression of the metabolism of clarithromycin. When co-administered with ritonavir, clarithromycin Cmax increased by 31%, Cmin increased by 182% and AUC increased by 77%, while the concentration of its metabolite 14-OH-clarithromycin was significantly reduced. Ritonavir should not be co-administered with clarithromycin in doses exceeding 1 g/day.

Clarithromycin, atazanavir, and saquinavir are substrates and inhibitors of CYP3A, which determines their bidirectional interaction. When taking saquinavir with ritonavir, consider the potential effect of ritonavir on clarithromycin.

When used simultaneously with zidovudine, the bioavailability of zidovudine is slightly reduced.

Colchicine is a substrate of both CYP3A and P-glycoprotein. Clarithromycin and other macrolides are known to be inhibitors of CYP3A and P-glycoprotein. When clarithromycin and colchicine are taken together, inhibition of P-glycoprotein and/or CYP3A may result in increased effects of colchicine. The development of clinical symptoms of colchicine poisoning should be monitored. There have been post-marketing reports of cases of colchicine poisoning when taken concomitantly with clarithromycin, most often in elderly patients. Some of the reported cases occurred in patients with renal failure. Some cases were reported to be fatal. The simultaneous use of clarithromycin and colchicine is contraindicated.

When midazolam and clarithromycin were used together (orally 500 mg 2 times a day), an increase in the AUC of midazolam was noted:

2.7 times after intravenous administration of midazolam and 7 times after oral administration. Concomitant use of clarithromycin with oral midazolam is contraindicated. If intravenous midazolam is used concomitantly with clarithromycin, the patient's condition should be carefully monitored for possible dose adjustment. The same precautions should be applied to other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination is not dependent on CYP3A (temazepam, nitrazepam, lorazepam), a clinically significant interaction with clarithromycin is unlikely.

When clarithromycin and triazolam are used together, effects on the central nervous system, such as drowsiness and confusion, are possible. With this combination, it is recommended to monitor symptoms of central nervous system disorders.

When used simultaneously with warfarin, the anticoagulant effect of warfarin may be enhanced and the risk of bleeding may increase.

Digoxin is thought to be a substrate for P-glycoprotein. Clarithromycin is known to inhibit P-glycoprotein. When used simultaneously with digoxin, there may be a significant increase in the concentration of digoxin in the blood plasma and the risk of developing glycoside intoxication.

Ventricular tachycardia of the “pirouette” type may occur with the combined use of clarithromycin and quinidine or disopyramide. When clarithromycin is coadministered with these drugs, ECG monitoring should be performed regularly to monitor for QT interval prolongation, and serum concentrations of these drugs should also be monitored. During post-marketing use, cases of hypoglycemia have been reported during co-administration of clarithromycin and disopyramide. It is necessary to monitor the concentration of glucose in the blood while using clarithromycin and disopyramide. It is believed that it is possible to increase the concentration of disopyramide in the blood plasma due to inhibition of its metabolism in the liver under the influence of clarithromycin.

Co-administration of fluconazole at a dose of 200 mg daily and clarithromycin at a dose of 500 mg 2 times a day caused an increase in the mean minimum equilibrium concentration of clarithromycin (Cmin) and AUC by 33% and 18%, respectively. However, co-administration did not significantly affect the average steady-state concentration of the active metabolite 14-OH-clarithromycin. No dose adjustment of clarithromycin is required when taking fluconazole concomitantly.

Clarithromycin and itraconazole are substrates and inhibitors of CYP3A, which determines their bidirectional interaction. Clarithromycin may increase plasma concentrations of itraconazole, while itraconazole may increase plasma concentrations of clarithromycin.

When used simultaneously with methylprednisolone, the clearance of methylprednisolone decreases; with prednisone - cases of acute mania and psychosis have been described.

When used simultaneously with omeprazole, the concentration of omeprazole increases significantly and the concentration of clarithromycin in the blood plasma increases slightly; with lansoprazole - glossitis, stomatitis and/or the appearance of a dark color of the tongue are possible.

When used simultaneously with sertraline, the development of serotonin syndrome cannot be theoretically excluded; with theophylline - it is possible to increase the concentration of theophylline in the blood plasma.

When used simultaneously with terfenadine, it is possible to slow down the rate of metabolism of terfenadine and increase its concentration in the blood plasma, which can lead to an increase in the QT interval and an increased risk of developing ventricular arrhythmias.

Inhibition of the activity of the CYP3A4 isoenzyme under the influence of clarithromycin leads to a slower rate of metabolism of cisapride when used simultaneously. As a result, the concentration of cisapride in the blood plasma increases and the risk of developing life-threatening cardiac arrhythmias, including ventricular arrhythmias, increases.

The primary metabolism of tolterodine is carried out with the participation of CYP2D6. However, in the part of the population lacking CYP2D6, metabolism occurs with the participation of CYP3A. In this population, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Therefore, in patients with low levels of CYP2D6-mediated metabolism, a reduction in the dose of tolterodine may be required in the presence of CYP3A inhibitors such as clarithromycin.

When clarithromycin is used together with oral hypoglycemic agents (for example, sulfonylureas) and/or insulin, severe hypoglycemia may occur. Concomitant use of clarithromycin with certain hypoglycemic drugs (for example, nateglinide, pioglitazone, repaglinide and rosiglitazone) may result in inhibition of CYP3A isoenzymes by clarithromycin, which may lead to hypoglycemia. It is believed that when used concomitantly with tolbutamide, there is a risk of developing hypoglycemia.

When used simultaneously with fluoxetine, a case of the development of toxic effects caused by the action of fluoxetine has been described.

When taking clarithromycin concomitantly with other ototoxic drugs, especially aminoglycosides, caution should be exercised and the functions of the vestibular and auditory systems should be monitored both during and after therapy.

When used simultaneously with cyclosporine, the concentration of cyclosporine in the blood plasma increases, and there is a risk of increased side effects.

When used simultaneously with ergotamine and dihydroergotamine, cases of increased side effects of ergotamine and dihydroergotamine have been described. Post-marketing studies show that when clarithromycin is used concomitantly with ergotamine or dihydroergotamine, the following effects associated with acute poisoning with drugs of the ergotamine group are possible:

vascular spasm, ischemia of the limbs and other tissues, including the central nervous system. Concomitant use of clarithromycin and ergot alkaloids is contraindicated.

Each of these PDE inhibitors is metabolized, at least in part, by CYP3A. However, clarithromycin can inhibit CYP3A. Concomitant use of clarithromycin with sildenafil, tadalafil or vardenafil may lead to an increase in the inhibitory effect on PDE. With these combinations, consider reducing the dose of sildenafil, tadalafil and vardenafil.

When using clarithromycin simultaneously with calcium channel blockers that are metabolized by the CYP3A4 isoenzyme (for example, verapamil, amlodipine, diltiazem), caution should be exercised as there is a risk of arterial hypotension. Plasma concentrations of clarithromycin, as well as calcium channel blockers, may increase with simultaneous use. Arterial hypotension, bradyarrhythmia and lactic acidosis are possible when taking clarithromycin and verapamil simultaneously.

Clarithromycin-OBL, 500 mg, film-coated tablets, 7 pcs.

Pharmacotherapeutic group: antibiotic, macrolide.

Pharmacodynamics: Clarithromycin is a second-generation bacteriostatic antibiotic from the group of broad-spectrum macrolides. Disturbs the protein synthesis of microorganisms (binds to the 50S subunit of the ribosomal membrane of the microbial cell). Acts on extra- and intracellularly located pathogens. Active regarding:

Streptococcus agalactiae (Streptococcus pyogenes, Streptococcus viridans, Streptococcus pneumoniae), Haemophilus influenzae (parainfluenzae), Haemophilus ducreyi, Neisseria gonorrhoeae, Neisseria meningitidis, Listeria monocytogenes, Legionella pneumophila, Mycoplasma pneumoniae, Helicobacter pylori (Campilobacter), Campi lobacter jejuni, Chlamydia pneumoniae, Moraxella catarrhalis, Bordetella pertussis, Propionibacterium acne, Mycobacterium avium, Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium marinom, Staphylococcus aureus, Ureaplasma urealyticum, Toxoplasma gondii, Corynebacterium spp., Borrelia burgdorferi, Pasteurella multocida, some anaerobes (Eubacterium spp. ., Peptococcus spp., Propionibacterium spp., Clostridium perfringens, Bacteroides melaninogenicus), is less active against Mycobacterium tuberculosis.

Pharmacokinetics: Absorption is rapid. Food slows absorption without significantly affecting bioavailability. Communication with plasma proteins is more than 90%. After a single dose, 2 peaks of the maximum concentration of the drug in the blood plasma are recorded. The second peak is due to the ability of the drug to concentrate in the gallbladder, followed by gradual or rapid entry into the intestine and absorption. The time to reach the maximum concentration of the drug in the blood plasma after oral administration of 250 mg is 1-3 hours.

After oral administration, 20% of the dose taken is quickly hydroxylated in the liver by cytochrome enzymes CYP3A4, CYP3A5 and CYP3A7 to form the main metabolite -14-hydroxyclarithromycin, which has pronounced antimicrobial activity against Haemophilus influenzae. It is an inhibitor of the isoenzymes CYP3A4, CYP3A5 and CYP3A7.

When taken regularly at 250 mg/day, the equilibrium concentrations of the unchanged drug and its main metabolite are 1 and 0.6 μg/ml, respectively; The half-life is 3-4 hours and 5-6 hours, respectively. When the dose is increased to 500 mg/day, the equilibrium concentration of the unchanged drug and its metabolite in plasma is 2.7-2.9 and 0.83-0.88 μg/ml, respectively; half-life is 4.8-5 hours and 6.9-8.7 hours, respectively. At therapeutic concentrations it accumulates in the lungs, skin and soft tissues (concentrations there are 10 times higher than the level in blood serum).

It is excreted by the kidneys and intestines (20-30% in unchanged form, the rest in the form of metabolites). With a single dose of 250 mg and 1200 mg, 37.9 and 46% are excreted by the kidneys, and 40.2 and 29.1% by the intestines, respectively.

Publications in the media

Clarithromycin (Klabax, Klatsid, Fromilid), granules for the preparation of an oral suspension, capsules, lyophilisate for the preparation of a solution for infusion, powder for the preparation of an oral suspension, film-coated tablets, film-coated tablets with extended release

Pharmaceutical group - macrolide antibiotic.

Pharmaceutical action. Semi-synthetic broad-spectrum macrolide antibiotic. Disturbs the protein synthesis of microorganisms (binds to the 50S subunit of the ribosomal membrane of the microbial cell). Acts on extra- and intracellularly located pathogens. Active against: Staphylococcus spp., Streptococcus agalactiae (Streptococcus pyogenes, Streptococcus viridans, Streptococcus pneumoniae), Haemophilus influenzae (Haemophilus parainfluenzae), Haemophilus ducreyi, Neisseria gonorrhoeae, Neisseria meningitidis, Listeria monocytogenes, Legionella pneumophila, Mycoplasma pneumonia e, Helicobacter pylori (Campylobacter ), Campylobacter jejuni, Chlamydia pneumoniae, Moraxella catarrhalis, Bordetella pertussis, Propionibacterium acne, Mycobacterium avium, Mycobacterium leprae, Mycobacterium cansasii, Mycobacterium marinom, Staphylococcus aureus, Ureaplasma urealyticum, Toxoplasma gondii, Corynebacterium spp., Borrelia burgdorferi, Pasteur ella multocida, some anaerobes (Eubacter spp., Peptococcus spp., Propionibacterium spp., Clostridium perfringens, Bacteroides melaninogenicus), less active against Mycobacterium tuberculosis.

Pharmacokinetics. Absorption is fast. Food slows absorption without significantly affecting bioavailability. The bioavailability of clarithromycin in suspension form is equivalent to or slightly higher than when taken in tablet form. Communication with plasma proteins is more than 90%. After a single dose, 2 Cmax peaks are recorded. The second peak is due to the ability of the drug to concentrate in the gallbladder, followed by gradual or rapid entry into the intestine and absorption. TCmax when taken orally 250 mg - 1-3 hours. After oral administration, 20% of the dose taken is quickly hydroxylated in the liver by cytochrome enzymes CYP3A4, CYP3A5 and CYP3A7 with the formation of the main metabolite - 14-hydroxyclarithromycin, which has pronounced antimicrobial activity against Haemophilus influenzae. It is an inhibitor of the isoenzymes CYP3A4, CYP3A5 and CYP3A7. With regular intake of 250 mg/day, Css of the unchanged drug and its main metabolite is 1 and 0.6 μg/ml, respectively; T1/2 - 3-4 and 5-6 hours, respectively. When the dose is increased to 500 mg/day, Css of the unchanged drug and its metabolite in plasma is 2.7-2.9 and 0.83-0.88 mcg/ml, respectively; T1/2 - 4.8-5 and 6.9-8.7 hours, respectively. At therapeutic concentrations it accumulates in the lungs, skin and soft tissues (concentrations there are 10 times higher than the level in blood serum). It is excreted by the kidneys and in feces (20-30% in unchanged form, the rest in the form of metabolites). With a single dose of 250 and 1200 mg, 37.9 and 46% are excreted by the kidneys, and 40.2 and 29.1% are excreted in the feces, respectively.

Indications. Lower respiratory tract infections (including bronchitis, pneumonia). Infections of the upper respiratory tract (including pharyngitis, sinusitis). Infections of the skin and soft tissues (including folliculitis, erysipelas). Mycobacterial infections caused by Mycobacterium avium and Mycobacterium intracellulare. Localized infections caused by Mycobacterium fortuitum and Mycobacterium kansasii. Prevention of the spread of infection caused by Mycobacterium avium complex (MAC infection) in HIV-infected patients with a CD4 lymphocyte count of no more than 100/μl. Eradication of Helicobacter pylori to reduce the frequency of relapses of duodenal ulcer. Odontogenic infections. For long-acting dosage forms: lower respiratory tract infections (including bronchitis, pneumonia), upper respiratory tract infections (including pharyngitis, sinusitis), skin and soft tissue infections (including folliculitis, erysipelas ).

Contraindications. Hypersensitivity, porphyria, pregnancy (first trimester), lactation, simultaneous use of cisapride, pimozide, terfenadine. Carefully. Renal and/or liver failure.

Dosing. Orally, adults and children over 12 years old - 250-500 mg 2 times a day. Duration of treatment is 6-14 days. In case of severe infections or in case of difficulty in oral administration, it is prescribed in the form of intravenous injections at a dose of 500 mg/day for 2-5 days, with further transfer to oral administration of 500 mg/day. The total duration of treatment is 10 days. When treating infections caused by Mycobacterium avium, 500 mg is prescribed orally 2 times a day. Duration of treatment is 6 months or more. Children are prescribed as a suspension at a dose of 7.5 mg/kg every 12 hours. The maximum daily dose is 500 mg. The duration of treatment is 7-10 days. In patients with chronic renal failure (creatinine clearance less than 30 ml/min or serum creatinine concentration more than 3.3 mg/100 ml) - 250 mg/day (once), for severe infections - 250 mg 2 times a day. The maximum duration of treatment for patients in this group is 14 days.

Side effect . From the nervous system: headache, dizziness, anxiety, fear, insomnia, nightmares; rarely - disorientation, hallucinations, psychosis, depersonalization, confusion. From the digestive system: nausea, vomiting, gastralgia, diarrhea, stomatitis, glossitis, increased activity of liver transaminases, cholestatic jaundice, rarely - pseudomembranous enterocolitis. From the senses: tinnitus, change in taste (dysgeusia); in isolated cases, hearing loss occurs after discontinuation of the drug. From the hematopoietic organs and hemostasis system: rarely - thrombocytopenia (unusual bleeding, hemorrhage). Allergic reactions: skin rash, itching, malignant exudative erythema (Stevens-Johnson syndrome), anaphylactoid reactions. Other: development of resistance of microorganisms.

Overdose. Symptoms: dysfunction of the gastrointestinal tract, headache, confusion. Treatment: gastric lavage, symptomatic therapy. Interaction. Simultaneous use with cisapride, pimozide, terfenadine is not allowed. When taken simultaneously, it increases the concentration in the blood of drugs metabolized in the liver with the help of cytochrome P450 enzymes - indirect anticoagulants, carbamazepine, theophylline, astemizole, cisapride, terfenadine (2-3 times), triazolam, midazolam, cyclosporine, disopyramide, phenytoin, rifabutin , lovastatin, digoxin, ergot alkaloids, etc. Reduces the absorption of zidovudine (an interval of at least 4 hours is required between the use of drugs). Cross-resistance may develop between clarithromycin, lincomycin and clindamycin.

Special instructions . In the presence of chronic liver diseases, it is necessary to regularly monitor serum enzymes. Prescribe with caution against the background of drugs metabolized by the liver (it is recommended to measure their concentration in the blood). In case of co-administration with warfarin or other indirect anticoagulants, it is necessary to monitor the prothrombin time.

Clinical pharmacology of clarithromycin: current issues in pediatric pulmonology

Macrolide antibiotics are widely used in children for various diseases due to their activity against many infectious agents and the presence of a number of therapeutically beneficial additional non-antibacterial properties. The semisynthetic 14-membered macrolide clarithromycin has been successfully used in pediatric practice for 25 years.

Antibacterial activity of clarithromycin

A clinically important pharmacological difference between clarithromycin and other macrolides is the formation of an active metabolite in the body - 14-hydroxyclarithromycin (14-HOCM), which also has antibacterial activity. With regard to sensitive pathogens, clarithromycin and its active metabolite exhibit an additive or synergistic effect. In this regard, the effect of an antibiotic in vivo may be higher than in vitro [1–2].

Like other macrolide antibiotics, clarithromycin has high activity against many gram-positive bacteria - staphylococci, streptococci (including pneumococci), listeria, corynebacteria, etc. Some gram-negative bacteria are sensitive to clarithromycin, like other macrolides - Moraxella catarrhalis, Bordetella pertussis, neisseria , Campylobacter jejuni. The activity of clarithromycin against Helicobacter pylori is higher than that of other macrolides. The activity of clarithromycin against Haemophilus influenzae is important - it is one of two macrolides (along with azithromycin) with clinically significant effectiveness against this pathogen. At the same time, the activity of clarithromycin in vitro against H. influenzae is low, but it is enhanced in vivo due to the action of 14-HOCM. Like other macrolides, clarithromycin is highly active against atypical bacteria - chlamydia, mycoplasma, legionella, rickettsia, ureaplasma. A clinically significant feature of clarithromycin is its high activity against Mycobacterium avium complex, the causative agent of mycobacteriosis. In addition, the drug is active against a number of anaerobic bacteria and toxoplasma [1–2].

The effect of clarithromycin is predominantly bacteriostatic, caused by disruption of protein synthesis on the ribosomes of sensitive bacteria. At the same time, in high doses the drug is able to have a bactericidal effect on a number of pathogens of respiratory infections - S. pyogenes, S. pneumoniae, H. influenzae, M. catarrhalis, L. pneumophila and M. avium. Clarithromycin has pronounced additional antimicrobial properties - a post-antibiotic effect and an effect on bacterial biofilms. Clarithromycin and 14-HOCM are characterized by a post-antibiotic effect against a number of bacteria, including key bacterial pathogens of respiratory infections - S. pneumoniae, H. influenzae and M. catarrhalis [1–2]. It has been established that clarithromycin, like some other macrolide antibiotics, can influence the virulence factors of Pseudomonas aeruginosa - the drug suppresses locomotor activity and the ability to form biofilms in this pathogen [3].

Non-antibacterial effects of clarithromycin

Experimental studies have established the mechanisms of action of clarithromycin, leading to the development of clinically beneficial non-antibacterial effects:

increased phagocytosis of apoptotic neutrophils by alveolar macrophages leads to the prevention of the release of neutrophil proteases and their effects on the respiratory tract [4];
suppression of the expression of intercellular adhesion molecules type 1 (ICAM-1) in the epithelium of the respiratory tract leads to a decrease in the accumulation of neutrophils in the pulmonary alveoli [5];
inhibition of the activation of nuclear transcription factor (NF-κB) in mononuclear blood cells and pulmonary epithelial cells is accompanied by suppression of the production of pro-inflammatory cytokines - tumor necrosis factor α (TNF-α), interleukins (IL) - IL-6, IL-8, etc. [ 6];
suppression of the expression of genes encoding inducible nitric oxide synthase (INOS) leads to a decrease in the formation of NO in the epithelium of the respiratory tract and alveolar macrophages [5];
a decrease in the level of IL-4 with an increase in the ratio of T helper cells type 1 and type 2 (Th1/Th2) [7];
reducing the influence of lipopolysaccharide (bacterial endotoxin) on goblet cells of the respiratory tract epithelium leads to a decrease in mucus hypersecretion [8];
inhibition of goblet cell hyperplasia in the airways induced by IL-13 also leads to a decrease in mucus hypersecretion [9].

Thus, clarithromycin has been shown to have immunomodulatory, anti-inflammatory and mucoregulatory effects, which is of great importance for the treatment of respiratory diseases of an infectious nature.

Pharmacokinetics of clarithromycin

After oral administration, the bioavailability of the drug is 52–55%, while food does not affect this indicator. The maximum concentration of clarithromycin in the blood after oral administration is observed on average after 2–3 hours. Clarithromycin is actively metabolized in the liver with the participation of cytochrome P450 with the formation of metabolites, the main of which is 14-HOCM. The binding of the drug to plasma proteins ranges from 42% to 70% (inversely dependent on the concentration in the blood). Both clarithromycin and 14-HOCM create high concentrations in tissues and biological fluids, including nasal secretions, tonsils, middle ear fluid, lung tissue, and sputum. In addition, high concentrations of the drug and its active metabolite are observed in phagocytes [1–2]. In a study that included 68 volunteers, the intrapulmonary pharmacokinetics of 4 antibacterial drugs were studied: clarithromycin (both the antibiotic itself and its active metabolite), azithromycin, ciprofloxacin and cefuroxime. 6 hours after a single standard dose of each drug (500 mg), clarithromycin and 14-HOCM had very high concentrations in alveolar cells, which exceeded the concentrations of all other antibiotics. In addition, clarithromycin was the only antibiotic found in the fluid lining the pulmonary epithelium [10]. The half-life of clarithromycin ranges from 3 to 8 hours, which is determined by the dose of the drug. From 20% to 40% of the drug is excreted in the urine unchanged, 10–15% in the form of metabolites. About 40% of the drug is excreted in feces [1–2].

Safety of clarithromycin use

For pediatric practice, the safety of drugs is of particular importance, since children may develop specific adverse reactions that are unusual for adult patients. Macrolide antibiotics extremely rarely cause severe adverse reactions and are rightfully considered one of the safest antibacterial drugs.

The safety of clarithromycin in children has been well established in clinical studies. When using the drug, undesirable reactions from the digestive system (diarrhea, nausea and vomiting, abdominal pain) are most often observed - their frequency can reach 15%. Headaches and increased transaminase levels may occur. Other reactions occurred in isolated cases. Adverse events when using clarithromycin are usually mild and short-lived and rarely require discontinuation of the drug [1–2].

In a retrospective study, 300 patients with allergic reactions to antibiotics were analyzed. It has been shown that patients with an allergy to macrolides are significantly less common in clinical practice than patients with an allergy to penicillins [11].

Of great interest is a retrospective cohort study that included 150 thousand people, in which the risk of adverse skin reactions to various antibacterial drugs was assessed [12]. Over 1.5 years, about 20 thousand courses of antibacterial therapy were carried out in this population in more than 13 thousand people, including more than 2 thousand children. Skin reactions were reported in 135 patients, representing approximately 1%. At the same time, the least likely adverse reactions from the skin were observed when using macrolides (the proportion of patients with skin reactions was 0.3%) - several times less than with penicillins, fluoroquinolones and co-trimoxazole (Fig.).

The issue of hepatotoxicity of macrolide antibiotics requires special attention, since cases of serious liver damage due to their use have been described [1]. In 2011, a review of the scientific literature was published that examined data on the hepatotoxicity of antibiotics. It has been shown that adverse reactions from the liver when using macrolides, penicillin, fluoroquinolones, tetracyclines are observed significantly less frequently than when using amoxicillin/clavulanate, co-trimoxazole, sulfonamides and anti-tuberculosis drugs. When using erythromycin and clarithromycin, the frequency of adverse hepatotoxic reactions is less than 4 cases per 100 thousand prescriptions, which is less than the average frequency of adverse events from the liver to antibacterial drugs. It has been noted that hepatotoxicity of antibiotics usually manifests itself when using high doses, long-term courses of treatment, in the elderly, in patients with underlying liver pathology, and with the simultaneous use of hepatotoxic drugs and alcohol [13].

When using clarithromycin, it must be taken into account that it has an inhibitory effect on cytochrome P450, which is involved in the metabolism of many drugs. When used simultaneously with such drugs, their concentration in the blood may increase and the risk of toxic effects may arise, as well as the effectiveness of clarithromycin may decrease [1–2].

Use of clarithromycin in pediatric practice

The original drug of clarithromycin Klacid® is registered in the Russian Federation for use in children in the form of film-coated tablets (250 and 500 mg) and powder for the preparation of an oral suspension (125 mg/5 ml and 250 mg/5 ml). The drug in oral form has no age restrictions, while the use of a suspension is recommended for children under 12 years of age; tablets are approved for use from the age of 12. The dose of the drug in children under 12 years of age is 15 mg/kg per day in two doses with an interval of 12 hours, but not more than 500 mg per day. In children over 12 years of age, the drug is prescribed at 250–500 mg every 12 hours. The duration of therapy, depending on the clinical situation, ranges from 5 to 14 days.

In pediatric practice, clarithromycin is recommended for the treatment of infectious diseases of various localizations caused by sensitive bacteria:

diseases of the upper respiratory tract and ENT organs - bacterial tonsillitis and pharyngitis, bacterial rhinosinusitis, acute otitis media [1–2, 14];
diseases of the lower respiratory tract - acute bronchitis, exacerbation of chronic bronchitis, pneumonia (the drug is included in the standards of medical care for patients with acute bronchitis and pneumonia of the Ministry of Health and Social Development in outpatient settings) [1–2, 15–17];
as part of eradication therapy for diseases of the gastrointestinal tract associated with H. pylori [1–2];
diseases of the skin and soft tissues [1–2];
diseases caused by M. avium (including for prevention) [1–2].

In general, the drug clarithromycin (Klacid®) remains of great importance in pediatric practice due to its high effectiveness in many infectious diseases and its favorable safety profile. The presence of additional therapeutically beneficial effects in the drug significantly expands the prospects for its use in respiratory pathology in children.

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Order of the Ministry of Health and Social Development of the Russian Federation dated February 12, 2007 No. 108 “On approval of the standard of medical care for patients with acute bronchitis.”
Order of the Ministry of Health and Social Development of the Russian Federation dated June 8, 2007 No. 411 “On approval of the standard of medical care for patients with pneumonia caused by Streptococcus pneumoniae; pneumonia caused by Haemophilus influenzae [Afanasyev-Pfeiffer bacillus]; bacterial pneumonia, not elsewhere classified; pneumonia caused by other infectious agents, not classified elsewhere; pneumonia without specifying the pathogen; lung abscess with pneumonia (when providing specialized care).”

N. A. Geppe, Doctor of Medical Sciences, Professor I. A. Dronov1, Candidate of Medical Sciences

GBOU VPO First Moscow State Medical University named after. I. M. Sechenova, Moscow

1 Contact information

Abstract. Macrolide antibiotics are widely used for treatment of different childish diseases due to active behavior against numerous pathogenic organisms and a number of useful for therapy additional non-antibacterial characteristics. Semisynthetic 14-member macrolide clarithromycin has been effectively used in pediatric practice for 25 years.

Clarithromycin in the treatment of urogenital mixed infections

inflammatory diseases of the genital and urinary organs, the etiological agents of which can be both pathogenic and opportunistic microorganisms, are one of the most common reasons for patients to turn to specialists.
Urogenital infections in women lead to serious disorders of reproductive function and infectious complications
in the form of inflammatory diseases of the pelvic organs, tubal infertility and ectopic pregnancy, and also affect the intrauterine development of the fetus, the outcome of childbirth and the course of the postpartum period. Monoinfection is rare, and its mixed forms lie in the genesis of all pathological changes occurring in the human body, especially in the urogenital tract.

For example, during an examination of 212 patients with tubal-peritoneal infertility, urogenital chlamydia was diagnosed in 49.5% of women, and when studying the microbiocenosis of the cervical canal in 77.1% of patients, in addition to chlamydia, enterococci, E. coli, ureaplasma, and gardnerella were found [6].

Other authors note that when examining patients with tubal infertility, chlamydia was found in 48%, of which in 44% of cases there was a combination with various other infectious agents: with mycoplasmas - 13.4%, Escherichia coli - 8%, Candida albicans

– 6%, with various types of staphylococci – 9.3% and streptococci – 7.3% [7].

Oral and intrauterine contraceptives, antibiotics, corticosteroid hormones, surgical interventions on the genitals, etc. contribute to the incidence of urogenital mixed infections.

Etiology and pathogenesis

Urogenital infection, due to the common transmission routes of pathogens, in most cases occurs as mixed with pathogenic (gonococci, trichomonas, herpes simplex virus) and opportunistic pathogens (ureaplasma, mycoplasma, anaerobes). Intracellular pathogens are of greatest interest

, such as chlamydia, mycoplasma, ureaplasma. Despite the differences in the biological properties of these pathogens, they all cause similar diseases of the urogenital tract.

They are characterized by:

tendency towards a long-term chronic course, often latent;
lack of stable immunity;
long-term carriage;
recurrent nature of the disease;
multi-symptom;
the presence of atypical or asymptomatic forms;
tendency for infection to spread;
similarity and severity of complications;
sexual route of infection;
the possibility of transplacental transmission of these infections to the fetus and newborn.

Chlamydia - tiny gram-negative bacteria with a unique intracellular development cycle - are unable to produce energy themselves and live off the energy of the host cell that they have infected. The vital activity of chlamydia is carried out through two stages of the life cycle: infectious extracellular forms and non-infectious intracellular forms. Elementary (infectious) bodies infect mainly cylindrical epithelial cells, after which they are reconstructed with the formation of metabolically active reticular bodies and, having passed the stage of intermediate forms, are replaced by elementary bodies. The full reproduction cycle of chlamydia is 48–72 hours.

Mycoplasmas belong to the family Mycoplasmataceae

.
This family is divided into two genera - the genus Mycoplasma
, which includes about a hundred species (for example,
M. hominis, M. genitalium
) and the genus
Ureplasma
, which has 3 species (for example,
U. urealiticum
). The manifestation of the pathogenic effect of mycoplasmas on the human body is associated with biological properties: small size, absence of a cell wall and the similarity of the structure of the cell membrane with the membranes of the cells of the host organism, which determines their penetration into the membrane of the body’s cells and makes them more protected from the effects of humoral and cellular immunity factors . These specific features can explain the uniqueness of this infection, which occurs predominantly latently and asymptomatically.

Urogenital infections are highly contagious

. For example, chlamydia is detected in 80% of women who were sexual partners of men infected with chlamydia. Patients who do not have pronounced symptoms of the disease pose a particular epidemiological danger with these infections. The incubation period for chlamydia is 2–3 weeks, and for mycoplasmosis from 3 to 5 weeks. The main routes of transmission are sexual, household contact (rare), and vertical.

Along with acute infection, a chronic process may develop. The type of development of the disease depends on the state of the person’s immunity, the severity of the infection, the pathogenicity and virulence of the infectious agent and many other reasons. Complications of urogenital mixed infection are pronounced disturbances of immunoregulation, associated in particular with suppression of the level of T-lymphocytes, T-helper cells, and a decrease in the level of interferon status of the patient.

Clinic

Clinical manifestations of urogenital associated infections caused by chlamydia, mycoplasma, and ureaplasma are quite wide: from asymptomatic carriage to severe inflammatory phenomena.

Bartholinitis

- inflammation of the large glands of the vestibule of the vagina - usually has a catarrhal character. Only the mouths of the excretory ducts of the gland are affected, but with a mixed infection with gonococci and pyogenic bacteria, an acute abscess of the large gland of the vestibule of the vagina sometimes develops with fever and severe pain.

Endocervicitis

– a frequent and typical manifestation of urogenital chlamydia. More often it is asymptomatic, but sometimes there is vaginal discharge and nagging pain in the lower abdomen. Erosion forms around the opening of the cervical canal, and mucopurulent discharge flows out of the canal. Often, peculiar lymphoid follicles (follicular cervicitis) are found in the pharynx area, which are not found in other urogenital infections.

Endometritis

– sometimes occurs in the postpartum or post-abortion period. In acute cases, body temperature rises to 38–39°C, pain in the lower abdomen, profuse mucopurulent discharge from the cervical canal appears, and the menstrual cycle is disrupted. Endometritis can occur chronically, without acute symptoms.

Salpingitis

– the most common manifestation of ascending infection. Inflammation can involve the ovaries (salpingoophoritis). These complications often occur subclinically and are detected only by a gynecologist during an examination in connection with infertility. Pain in the lower abdomen, vaginal discharge, menstrual irregularities, and dysuric phenomena are sometimes observed. In acute salpingitis, the body temperature rises to 38–39°C, the general condition is disturbed, the ESR increases, leukocytosis is detected, etc.

Pelveoperitonitis

– occurs quite often with ascending infection. It can occur subclinically and acutely, with sharp pain, initially localized in the lower abdomen, tension in the abdominal wall, increased body temperature, etc. Acute pelveoperitonitis can be provoked by medical abortion, childbirth, surgical interventions that exacerbated a latent urogenital infection.

Urogenital chlamydia in women can cause ectopic (ectopic) pregnancy. Mixed infection in the early stages of pregnancy sometimes leads to spontaneous abortion, and infection in the later stages leads to fetal malnutrition, premature rupture of amniotic fluid, and chorioamnionitis.

Diagnostics

Laboratory diagnosis of urogenital infections is varied. The most frequently used diagnostic methods are: cytological, serological, and the method of isolating the pathogen in cell cultures.

When chlamydial, mycoplasma, or ureaplasma infections are detected in women, it is necessary to examine partners who have had sexual contact with them. One of the most critical diagnostic stages is the collection of material. It is this stage that should be carried out in medical institutions of the widest profile, while further processing of the material can be carried out in specialized laboratories. The analysis should be taken with a special brush from the cervical canal of the cervix after removing the mucus plug.

A simple, but not sensitive enough diagnostic method is staining the material using the Romanovsky-Giemsa method. It is possible to diagnose chlamydial infection using this method on average only in 15% of men and 40% of women, especially when collecting material from the cervical canal.

The serological method allows you to detect antibodies in the blood. In acute infection, the detection of specific antibodies of class M immunoglobulins or a fourfold increase in titers of class G immunoglobulins over time, after 2 weeks, are of diagnostic importance. When interpreting the data obtained, one cannot assert infection solely on the basis of the presence of antibodies, just as negative results of serological tests do not exclude the presence of current or past infection.

According to WHO recommendations (1982), the best diagnostic method is

lesions of the genitourinary tract is
the isolation of the pathogen in a cell culture treated with antimetabolites
. Abroad, most laboratories use a culture of McCoy cells treated with cycloheximide. After 48–60 hours, the cells are fixed and stained using one of the methods or the immunofluorescence method. The advantages of this method are 100% specificity and sensitivity. However, the widespread use of this method is hampered by its complexity, relative high cost, and the possibility of obtaining results no earlier than 72 hours.

Enzyme immunoassay is based on the detection of genus-specific lipopolysaccharide. Sensitivity is 80–95%, specificity is 90%. The advantage of this method is the possibility of using it for screening examination.

Molecular biological methods, in particular the PCR method, are based on identifying the DNA of pathogens in samples by hybridization. The sensitivity and specificity of this method are high (80–100%). A special feature of the method is the need for special equipment. These laboratories require strict certification.

For correct diagnosis and control of cure, a combination of various laboratory diagnostic methods is necessary.

Treatment

Treatment of urogenital co-infections is a complex and difficult task. Monoinfection is quite rare, and very often it is aggravated by association with other sexually transmitted infections.

When observing 203 women who suffered from inflammatory diseases of the urogenital tract and infertility, a high frequency of mixed infections in the genesis of infertility was confirmed. The authors found urogenital chlamydia in 29.5% of patients. Chlamydia in women as a monoinfection occurred in 2.5% of cases, and in combination with gardnerellosis - in 88.3%, and of the 98 detected cases of gardnerellosis in patients, mixed forms with 2 or 3 infections (mycoplasma, ureaplasma, etc.) accounted for 61, 3% of the specified mixed forms [2].

A high degree of participation of associated infections in the occurrence and development of inflammatory diseases of the pelvic organs, the ability of microorganisms to mutually “aggravate” the course of the underlying disease and its outcome, and difficulties arising in the treatment of associated forms were also noted.

Intracellular pathogens have a high tropism for epithelial cells in lesions and persist in special membrane-limited zones of the epithelium, which is a prerequisite for pathogens to survive the period of drug therapy and can lead to treatment failures. This necessitates the use of not only etiotropic but also pathogenetic agents, taking into account the possibility of the disease transitioning to an asymptomatic and latent state.

Therapy involves the inclusion in the complex of therapeutic agents of an immunomodulator (thymalin, diaphenylsulfone, etc.), an antibiotic and a drug to prevent the development of candidal lesions. Currently, preference is given to antibiotics capable of intracellular accumulation (tetracyclines, fluoroquinolones, macrolides).

Let us dwell in more detail on the group of macrolides, since they are among the safest antibiotics

. They are characterized by a small number of side effects and good tolerability.

Spectrum of action of macrolides:

– gram-positive bacteria;

– gram-negative bacteria, except enterobacteriaceae;

– intracellular pathogenic microorganisms ( C. pneumoniae, M. pneumoniae, C. trachomatis, M. hominis, M. genitalium, U. urealiticum

and etc.).

, clarithromycin (Fromilid) attracts special attention.

– semi-synthetic acid-resistant antibiotic. It should be emphasized that the pharmacological feature of macrolides, including clarithromycin, is their ability to overcome cell membranes and accumulate in the cells of the macroorganism, including immunocompetent cells. The high clinical effectiveness of clarithromycin (Fromilid) is associated with its anti-inflammatory effect and impact on the functional activity of peripheral blood phagocytes, which is likely due to their pronounced antioxidant activity and the ability to reduce oxidative metabolism in phagocytes, reducing the formation of superoxide ion. In addition, clarithromycin affects the processes of the immune response of the macroorganism through changes in the synthesis by monocytes and macrophages of the most important mediators of the immune response, such as tumor necrosis factor, interleukins, colony-stimulating factor, etc., which allows it to be considered an antibiotic with an immunomodulatory effect on the human body.

If, for example, we take two antibiotics of the same group, such as clarithromycin and erythromycin, and compare them, the first is superior to the second in pharmacokinetics, as evidenced by its better absorption in the intestine, higher plasma concentration and long half-life, as well as enhanced penetration in fabric. Clarithromycin is approximately 8 times more active against intracellular pathogens

, which provides more convenient double use of the drug in outpatient practice.

Back in 1988, Japan conducted a study of the effectiveness of clarithromycin in a group of patients with urogenital infections who were under the supervision of a number of clinics and medical practitioners. According to the combined data, of 204 patients with chlamydial urethritis who received clarithromycin at a daily dose of 200 to 900 mg for 3–14 days, the clinical effect was excellent or good in 188, i.e. in 92%. In addition, out of 116 patients with urethritis caused by ureaplasma, cure was achieved in 99, i.e. in 85%.

E. Calzolari et al reported the results of treatment with clarithromycin for endocervicitis and endurethritis in patients with intracellular infections. In 51 (100%) patients, ELISA results were negative 7–10 days after the end of clarithromycin therapy (500 mg 2 times a day for 7 days). Of the 64 women (control group) who received erythromycin (1 g 2 times a day for 7 days), only 88% of patients had a negative ELISA result at the same time.

Thus, clarithromycin (Fromilid) is an effective remedy in the fight against associated urogenital infection

allowing to achieve success in treating patients.
Further work on the use of clarithromycin may lead to a significant shift in the problem of treating urogenital mixed infections. Literature:
1. Delectorsky V.V., Yashkova G.N., Mazurchuk S.A. // Chlamydia. Bacterial vaginosis. (Clinic–diagnosis–treatment). – M., 1995. – 30 p.

2. Zalessky M.G., Krylova M.P., Sergeeva S.M. and others. Polymerase chain reaction in the diagnosis and control of treatment of infectious diseases: Sat.tr. 2nd All-Russian scientific-practical. conf. M., 1998,36

3. Kozlova V.I., Puchner A.F. // Viral, chlamydial and mycoplasma diseases of the genitals. – M., 1995. – P. 174–178.

4. Kovalev V.M., Krivenko Z.F., Ivanova I.P. Act. scientific problems and practical dermatology and venereology. 1994; 5:66.

5. Mavrov I.I., Shatilov A.V. Vestn. dermatol. and venerol. 1994; 4:15–8.

6.Medvedev B.I., Astakhova T.V., Lysenko S.V. and others. Akush. And gynecol. 1993.5: 36–9.

7. Romashchenko O.V. The role of chlamydial infection in the occurrence of female infertility: Abstract of thesis. dis….cand. honey. Sci. Kyiv, 1989; 21 p.

8. Revunov V.P. Act. problem scientific and practical dermatology and venereology. 1994; 5:66

9. Moricawa K, Watabe H, Araake M, Moricawa S. Antimicrob Agents Chemother 1996; 40(6):1366–70.

10. Calzolari E, Ciampaglia G, Steffe M. et al. Drugs Exp Clin Res 1992; 18 (10): 427–30.

Currently, in many countries of the world, including Russia, there is an increase in sexually transmitted infections (STIs), which occupy one of the first places in the structure of obstetric and gynecological morbidity [3, 7, 11, 14].

Most often, genital infection is caused by several pathogenic factors: viruses, microbes, fungi and protozoa, which cause diseases that are similar in clinical course, but different in pathogenesis and treatment methods [7, 11].

Despite significant advances made in the diagnosis, treatment and prevention of these infections, their frequency does not have a clear downward trend [2, 4, 13]. To a certain extent, this is due to the increase in immunodeficiency conditions against the backdrop of deteriorating environmental conditions, poor nutrition, frequent stress, a pharmacological boom with the uncontrolled use of drugs, primarily antibiotics, etc. [1, 5, 9, 10].

The introduction of modern technologies into clinical practice has made it possible to expand the range of studies conducted and show that the negative impact of environmental factors on the microflora of the macroorganism leads to the development of various pathological conditions of both inflammatory and non-inflammatory origin [2, 8, 12].

Vaginal dysbiosis and similar changes in the gastrointestinal tract, urinary system, psycho-emotional disorders, the formation of immuno- and interferon-deficiency states - this is not a complete list of problems characteristic of women with urogenital infection. The presence of these problems does not allow for the formation of adequate compensatory and adaptive reactions in the majority of these patients [7, 11].

The results of studies conducted at the Scientific Center for Obstetrics, Gynecology and Perinatology of the Russian Academy of Medical Sciences largely correspond to the available literature data. The combination of chlamydia with gonococcus is observed in 33.7% of patients, with ureamicoplasmosis - in 19.1%, with Gardnerella - in 9.9%. At the same time, three different infections are diagnosed in 10.6% of patients, 4–5 infections – in 5.6% [2, 8]. The most commonly diagnosed genitourinary tract infection is chlamydia.

Chlamydia ( Chlamydia trachomatis

) are small gram-negative bacteria. They are absolutely pathogenic for humans and are obligate intracellular parasites. Chlamydia exhibits the greatest tropism for columnar epithelial cells, causing infections of the urogenital tract, respiratory organs, and conjunctiva of the eyes. In a number of countries, chlamydia is isolated from 40% of men with nongonococcal urethritis [14]. In women with cervicitis, chlamydia is isolated in 36% of cases, and with cervical ectopia - in 47%. According to

B.L. Gurtova et al. [2], in patients with urethritis and/or cystitis, chlamydia is isolated in 21.7% of cases. The 8.9% increase in genital inflammatory disease observed in the UK is primarily due to chlamydial infection [11].

The main route of infection in adults is sexual, but it is possible to become infected with chlamydia through household means. Chlamydia is one of the infectious diseases that develop against the background of acquired or congenital immunodeficiency. Lesions of the lower urogenital tract include chlamydial urethritis, paraurethritis, bartholinitis, colpitis and cervicitis. The latter is the primary and most common manifestation of chlamydial infection. However, clinical signs of cervicitis - swelling and hyperemia of the cervix, specific mucopurulent discharge from the genital tract - are observed only in a third of women.

In most cases, the infection is asymptomatic [3, 4, 14].

Ascending chlamydial infection affects the mucous membrane of the uterus and tubes; ovaries, ligamentous apparatus of the uterus, peritoneum, liver. The most common manifestation of such an infection is chlamydial salpingitis. Its peculiarity is a long-term subacute, erased course without a tendency to worsen in the absence of a pronounced adhesive process in the area of the pelvic organs. The most dangerous complication of chlamydial salpingitis is infertility [2, 13].

The next most frequently detected representatives of microorganisms that cause inflammatory diseases of the genital organs are myco- and ureaplasmas. Humans are the natural host of at least 11 species of mycoplasmas, 3 of which are Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma urealyticum

– can cause inflammatory diseases of the urogenital tract.
Most mycoplasmas are classified as opportunistic microorganisms. Distinctive features of mycoplasmas and ureaplasmas are the absence of a cell wall and the ability to parasitize the membrane of host cells. Urogenital mycoplasmosis is quite widespread in the population. Carriage of M. hominis
and
U. urealyticum
among the population varies from 10 to 50% [8, 11, 14].
The main route of transmission of infection is sexual, and most often mycoplasmas are found in individuals with increased sexual activity. The leading role in the development of the infectious process is played not so much by the very fact of the presence or absence of mycoplasmas, but by the breadth and massiveness of their dissemination. The virulence of a particular strain also plays an important role in the development of infection. Asymptomatic carriage of mycoplasmas is widespread among healthy individuals. In many cases, they cause a latent infection, which, under the influence of various stress factors, can develop into a chronic recurrent or acute form. It is important to note that as a monoinfection, mycoplasmosis occurs only in 12–18% of cases, and in association with other pathogenic microbes – in 82–88%, including chlamydia – in 18–20%. The role of mycoplasmas in the development of urethritis, pyelonephritis and urolithiasis ( U. urealyticum
), as well as postpartum endometritis (
M. hominis
) has been definitively proven [2, 11].

One of the most difficult problems today remains the search for new effective drugs for the treatment of urogenital infections. Numerous studies are devoted to the development of schemes and methods for using certain antimicrobial drugs for these diseases. Attempts are being made to optimize therapy using immunomodulators, enzymes and other drugs.

Based on the characteristics of sexually transmitted infections presented above, their therapy should be comprehensive, and the drugs used should have a wide spectrum of action.

The rational choice of antibiotics should be made taking into account the following criteria [5, 6, 10, 12]:

spectrum of activity corresponding to the suspected pathogen;
pharmacokinetics, which determines the penetration of the antibiotic into the inflammation, frequency of administration and duration of treatment;
effectiveness against urogenital infections, proven in randomized clinical trials;
contraindications and frequency of side effects;
ease of use for the patient (increases accuracy of adherence to the treatment regimen); cost efficiency.

Taking into account the main pathogens of STIs, the following promising groups of antibiotics for their treatment can be identified: aminopenicillins, cephalosporins, macrolides, fluoroquinolones.

The role of macrolides and fluoroquinolones in the treatment of urogenital infections is discussed in detail in domestic and foreign literature [1, 2, 6, 9, 12].

As an alternative to tetracyclines, the macrolide antibiotic erythromycin has been used for a long time. According to published data, therapy with this drug remains quite effective today - 83–95% [6, 13], however, many authors [1, 2, 6, 13] note that pronounced side effects from the gastrointestinal tract, as well as a high course dose and the need for multiple doses (4 times a day, 500 mg) reduce the acceptability of its use.

According to the recommendations of the American Center for Disease Prevention and Control, amoxicillin is an alternative drug used in the treatment of urogenital infections [11]. However, despite the reported relatively high cure rates with amoxicillin - 82–94%, we should not forget that in vitro penicillins have an incomplete inhibitory effect against C. trachomatis

,
M. hominis
and
U. urealyticum
[5, 8, 11].

The benchmark for the effectiveness of various treatment regimens is oral doxycycline (100 mg 2 times a day for 7 days). Isolation of pathogens resistant to its action is extremely rare. However, the use of this drug may be accompanied by a number of side effects.

The use of roxithromycin (300 mg 1 time per day) or josamycin (500 mg 2 times per day) is not inferior in effectiveness to the standard regimen of doxycycline. In addition, josamycin can be used to treat pregnant women.

In recent years, the successful use of clarithromycin in women with chlamydial and ureamycoplasma infections has been widely reported in the literature [4, 6, 9, 12].

Clarithromycin is a semi-synthetic 14-membered macrolide, a derivative of erythromycin A. It was developed by the pharmaceutical company Taisho (Japan) in 1991.

Clarithromycin is 6-0-methylerythromycin (see figure). The presence of a methoxy group at position 6 of the lactone ring gives it increased acid stability and improved antibacterial and pharmacokinetic properties compared to erythromycin. The resistance of clarithromycin to the hydrolyzing action of hydrochloric acid is 100 times higher than that of erythromycin, however, the drug exhibits its maximum antibacterial effect in an alkaline environment.

An important feature of clarithromycin is the formation of an active metabolite in the body - 14-hydroxyclarithromycin, which also has antibacterial activity. The mechanism of action of clarithromycin does not differ from other macrolide antibiotics.

According to some researchers [6, 9, 10], clarithromycin has a “balanced” antibacterial effect, showing activity against pathogens with both extracellular and intracellular localization. In terms of the spectrum of antibacterial activity, it is close to erythromycin (like erythromycin, clarithromycin has little activity against M. hominis

[6, 10, 12]), although it has some differences.

Clarithromycin is approximately 8 times more active than erythromycin against C. trachomatis [6, 10]. In addition, it is stronger than erythromycin against Chlamydia psittaci

. Compared to erythromycin, clarithromycin is more active against U. urealyticum.

It has been established that clarithromycin is able to interact with the immune system of the macroorganism. In particular, it increases the phagocytic activity of neutrophils and macrophages, to a greater extent than erythromycin and josamycin [9]. A synergistic bactericidal effect was revealed when clarithromycin was combined with blood serum complement. In addition, in the presence of clarithromycin, the activity of killer T cells increases, which may likely be important in the treatment of bacterial infections complicated by viral superinfections [2, 12].

Penetrating into many organs and tissues, clarithromycin, like other macrolides, creates high concentrations inside cells, which is the basis for suppressing intracellularly proliferating pathogens such as chlamydia, legionella and toxoplasma. Accumulating in immunocompetent cells, the antibiotic, as noted above, enhances their phagocytic function.

The effectiveness of clarithromycin in the treatment of urogenital infections has been studied in several controlled studies. The best clinical effect was observed in chlamydial urethritis and cervicitis [2, 6, 9]. In patients with urethritis caused by U. urealyticum

, the use of this antibiotic is also very successful.
At the same time, the effectiveness of clarithromycin for urethritis of gonorrheal nature or having a mixed etiology (chlamydia + gonococci) seems insufficient [13]. G.A. Dmitriev [3], A. Barry et al. [9] showed that the use of 250 mg of clarithromycin 2 times a day for 7 days led to the disappearance of C. trachomatis, M. hominis, U. urealyticum
from the genital tract of men and women.

Our experience in using clarithromycin 250 mg 2 times a day or 500 mg 1 time a day (slow-release tablets) indicates the high effectiveness of this antibiotic in the treatment of urogenital infections caused by chlamydia and various types of mycoplasmas, especially when cervicitis is combined with cystitis or pyelonephritis .

It has been proven that clarithromycin is a highly effective macrolide antibiotic that can be used both orally and parenterally. It has the following advantages over erythromycin: stability in an acidic environment; more stable bioavailability, independent of food intake; smaller frequency of application (1–2 times a day). Clarithromycin is better tolerated than erythromycin. The overall incidence of adverse reactions caused by clarithromycin is 10–12% [6, 9]. The most common side effects associated with its use are from the gastrointestinal tract: nausea, diarrhea, dyspepsia, abdominal pain. In rare cases, patients may experience headaches, vomiting, changes in taste sensitivity, a taste of bile in the mouth, enlarged liver, and allergic reactions. It is important to emphasize that in most cases the severity of side effects of clarithromycin is regarded as mild or moderate [6]. In 2% of patients, changes in the activity of liver transaminases of varying severity may be observed. As comparative studies have shown, these violations occur less frequently than with the use of another macrolide, josamycin.

Due to the peculiarities of pharmacokinetics and a unique spectrum of antimicrobial action, covering the main causative agents of genitourinary tract infections, clarithromycin is the drug of first choice in the treatment of sexually transmitted diseases and provides effective treatment of co-infections [2, 6, 10, 12].

It is advisable to combine etiotropic therapy for infectious pathologies of the reproductive system with the use of antioxidants - ascorbic acid (vitamin C) 50 mg and vitamin E 100 mg 3 times a day. It is also possible to use efferent treatment methods (plasmapheresis, endovascular laser irradiation of blood, the use of medical ozone). When treating with antibacterial drugs, special attention should be paid to restoring the microecology of the genital tract.

Thus, to summarize the above, clarithromycin is one of the most effective and safe antibiotics for the treatment of urogenital infections. Its high clinical effectiveness allows us to consider this antibiotic one of the main means for the treatment of sexually transmitted diseases. At the same time, there is no doubt about the need to further improve treatment regimens and methods for urogenital infections.