Indications and spectrum of action
Clarithromycin is used to treat bacterial infections of the respiratory system (such as bronchitis or pneumonia), ear, nose, and throat (such as tonsillitis or sinusitis), and skin (such as impetigo or erysipelas).
Clarithromycin is active against streptococci (including pneumococci), legionella, chlamydia, bacteria without a cell wall (for example mycoplasma), atypical mycobacteria, as well as Bordetella pertussis.
The clinical effectiveness of all macrolides against Haemophilus influenzae is currently considered insufficient.
Clarithromycin is also used in combination therapy to destroy Helicobacter pylori colonies in the gastric mucosa (gastritis).
Contraindications
Due to the predominance of metabolism in the liver, the use of clarithromycin is contraindicated in patients with severe hepatic impairment.
The use of clarithromycin is contraindicated if there is hypersensitivity to clarithromycin or other macrolide antibiotics (for example, azithromycin).
General use with cisapride, pimozide, terfenadine, or astemizole is prohibited because life-threatening arrhythmias may occur.
In addition, clarithromycin should not be taken with the ergot alkaloids dihydroergotamine and ergotamine. Combined use may lead to intoxication and vasospasm.
Interactions with other drugs
Because clarithromycin inhibits the activity of the cytochrome P450 isoenzyme CYP3A4, the metabolism of many other drugs may be slowed. As a result, their concentration increases and the effect intensifies. There are a huge variety of such drugs, here are the most common examples:
- quinidine and disopyramide,
- anticonvulsant carbamazepine,
- anti-gout remedy - colchicine,
- cardiac glycoside - digoxin,
- statins,
- anticoagulants,
- sildenafil, tadalafil and vardenafil,
- theophylline,
- tolterodine,
- benzodiazepines (triazolbenzodiazepines, e.g. midazolam, triazolam, alprazolam),
- antivirals – zidovudine, atazanavir, saquinavir,
- proton pump blocker omeprazole,
- calcium antagonists,
- itraconazole and others.
Concomitant use of all these drugs with clarithromycin should be carefully monitored.
Clarithromycin
The simultaneous use of clarithromycin and the following drugs is contraindicated due to the possibility of serious side effects.
Cisapride, pimozide, terfenadine and astemizole
When clarithromycin was taken together with cisapride, pimozide, terfenadine, astemizole, an increase in the concentration of the latter in the blood plasma was reported, which can lead to an increase in the QT interval and the appearance of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and torsade de pointes (see section "Contraindications").
Ergot alkaloids
When clarithromycin is used together 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. The simultaneous use of clarithromycin and ergot alkaloids is contraindicated (see section "Contraindications").
HMG-CoA reductase inhibitors (statins)
Co-administration of clarithromycin with lovastatin or simvastatin is contraindicated (see section "Contraindications") due to the fact that these statins are largely metabolized by the CYP3A4 isoenzyme, and combined use 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 statins. It is recommended to use statins that do not depend on CYP3A metabolism (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.
Effect of other drugs on clarithromycin
Drugs that are CYP3A inducers (for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) may induce the metabolism of clarithromycin. This may result in subtherapeutic concentrations of clarithromycin, resulting in reduced effectiveness. In addition, it is necessary to monitor the concentration of the CYP3A inducer in the blood plasma, which may increase due to inhibition of the CYP3A isoenzyme by clarithromycin. When rifabutin and clarithromycin were used together, an increase in plasma concentrations of rifabutin and a decrease in serum concentrations of clarithromycin were observed with an increased risk of developing uveitis.
The following drugs have a proven or suspected effect on clarithromycin plasma concentrations; if used concomitantly with clarithromycin, dosage adjustments or switching to alternative treatment may be required.
Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine
Strong inducers of the cytochrome P450 system, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentine, can accelerate the metabolism of clarithromycin and, thus, reduce the plasma concentration of clarithromycin and weaken the therapeutic effect, and at the same time increase the concentration of the 14-OH-clarithromycin metabolite, also being 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.
Etravirine
The concentration of clarithromycin decreases with the use of etravirine, but the concentration of the active metabolite 14-OH-clarithromycin increases. Because 14-OP-clarithromycin has low activity against Mycobacterium avium complex (MAC) infections, overall activity against these pathogens may be affected, and alternative treatments should be considered for the treatment of MAC.
Fluconazole
Coadministration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in an increase in mean clarithromycin minimum steady-state concentration (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.
Ritonavir
Coadministration of ritonavir 200 mg every eight 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%. Complete suppression of the formation of 14-OH-clarithromycin was noted. Due to the wide therapeutic range of clarithromycin, dose reduction is not required in patients with normal renal function. In patients with renal failure, it is advisable to consider the following dose adjustment options: with creatinine clearance of 30-60 ml/min, the dose of clarithromycin should be reduced by 50%; if creatinine clearance is less than 30 ml/min, the dose of clarithromycin should be reduced by 75%. Ritonavir should not be co-administered with clarithromycin in doses exceeding 1 g/day.
Effect of clarithromycin on other drugs Antiarrhythmic drugs (quinidine and disopyramide)
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, the electrocardiogram should be regularly monitored for prolongation of the QT interval, 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.
Oral hypoglycemic agents and insulin
When clarithromycin is used together with oral hypoglycemic agents (for example, sulfonylureas) and/or insulin, severe hypoglycemia may occur. During concomitant use of clarithromycin and certain drugs that lower glucose concentrations, such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of the CYP3A isoenzyme by clarithromycin may occur, which may result in hypoglycemia. Careful monitoring of glucose concentrations is recommended.
Interactions due to CYP 3 A
Co-administration of clarithromycin, which is known to inhibit the CYP3A isoenzyme, and drugs primarily metabolized by the CYP3A isoenzyme, may be associated with a mutual increase in their concentrations, which may increase or prolong both therapeutic and side effects. Clarithromycin should be used with caution in patients receiving drugs that are substrates of the CYP3A isoenzyme, especially if these drugs have a narrow therapeutic index (for example, carbamazepine) and/or are extensively metabolized by this enzyme. If necessary, the dose of the drug taken together with clarithromycin should be adjusted. Also, whenever possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored.
The following drugs/classes are metabolized by the same CYP3A isoenzyme as clarithromycin, for example, alprazolam, carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, midazolam, omeprazole, indirect anticoagulants (eg, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, triazolam and vinblastine. Also, agonists of the CYP3A isoenzyme include the following drugs that are contraindicated for combined use with clarithromycin: astemizole, cisapride, pimozide, terfenadine, lovastatin, simvastatin and ergot alkaloids (see section “Contraindications”). Drugs that interact in this manner through other isoenzymes within the cytochrome P450 system include phenytoin, theophylline, and valproic acid. Co-administration of clarithromycin, which is known to inhibit the CYP3A4 isoenzyme, and quetiapine, which is a CYP3A4 substrate, may lead to increased exposure of the antipsychotic quetiapine and possible toxic effects.
There have been post-marketing reports of somnolence, orthostatic hypotension, altered states of consciousness, neuroleptic malignant syndrome, and QT prolongation when these drugs are used together.
Caution should be used when quetiapine is used in combination with CYP3A4 inhibitors such as clarithromycin. The dose of quetiapine may need to be reduced.
Indirect anticoagulants
When taking warfarin and clarithromycin together, bleeding and a marked increase in the international normalized ratio (INR) and prothrombin time are possible. In case of combined use with warfarin or other indirect anticoagulants, it is necessary to monitor the INR and prothrombin time.
Omeprazole
Clarithromycin (500 mg every 8 hours) was studied in healthy adult volunteers in combination with omeprazole (40 mg daily). When clarithromycin and omeprazole were used together, steady-state plasma concentrations of omeprazole were increased (Cmax, AUCo-24 and T1/2 increased by 30%, 89% and 34%, respectively). The mean 24-hour gastric pH was 5.2 when omeprazole was taken alone and 5.7 when omeprazole was taken with clarithromycin.
Sildenafil, tadalafil and vardenafil
Each of these phosphodiesterase-5 inhibitors is metabolized at least in part by CYP3A. However, CYP3A may be inhibited in the presence of clarithromycin. Concomitant use of clarithromycin with sildenafil, tadalafil or vardenafil may result in increased phosphodiesterase inhibitory effects. When using these drugs together with clarithromycin, consider reducing the dose of sildenafil, tadalafil and vardenafil.
Theophylline, carbamazepine
When clarithromycin and theophylline or carbamazepine are used together, the concentration of these drugs in the systemic circulation may increase.
Tolterodine
The primary metabolism of tolterodine occurs through the 2D6 isoform of cytochrome P450 (CYP2D6). However, in part of the population lacking the CYP2D6 isoenzyme, metabolism occurs through CYP3A. In this population, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. In populations that are poor metabolizers via CYP2D6, a reduced dose of tolterodine may be required in the presence of CYP3A inhibitors such as clarithromycin.
Benzodiazepines (eg, alprazolam, midazolam, triazolam)
When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC increased by 2.7 times after intravenous midazolam and 7 times after oral administration. Concomitant oral administration of midazolam and clarithromycin should be avoided. 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, central nervous system (CNS) effects such as drowsiness and confusion are possible. Therefore, if coadministration occurs, it is recommended to monitor for symptoms of CNS impairment.
Interactions with other drugs
Aminoglycosides
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.
Colchicine
Colchicine is a substrate of both CYP3A and the P-glycoprotein (Pgp) transporter protein. Clarithromycin and other macrolides are known to be inhibitors of CYP3A and Pgp. When clarithromycin and colchicine are taken together, inhibition of Pgp 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 suffering from kidney failure. Some cases were reported to be fatal. The simultaneous use of clarithromycin and colchicine is contraindicated (see section "Contraindications").
Digoxin
Digoxin is suspected to be a Pgp substrate. Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may result in increased effects of digoxin. Coadministration of digoxin and clarithromycin may also result in increased serum concentrations of digoxin. Some patients have experienced clinical symptoms of digoxin toxicity, including potentially fatal arrhythmias. When clarithromycin and digoxin are used together, serum digoxin concentrations should be carefully monitored.
Zidovudine
Concomitant use of clarithromycin tablets and oral zidovudine in adult HIV-infected patients may result in decreased steady-state zidovudine concentrations.
Because clarithromycin interferes with the oral absorption of zidovudine, the interaction can be largely avoided by taking clarithromycin and zidovudine 4 hours apart.
This interaction was not observed in HIV-infected children taking clarithromycin pediatric suspension with zidovudine or dideoxyinosine. Since clarithromycin may interfere with the absorption of zidovudine when administered concomitantly orally in adult patients, such an interaction is unlikely to occur when clarithromycin is used intravenously.
Phenytoin and valproic acid
There is evidence of interactions between CYP3A inhibitors (including clarithromycin) and drugs that are not metabolized by CYP3A (phenytoin and valproic acid). For these drugs, when used together with clarithromycin, it is recommended to determine their serum concentrations, as there are reports of their increase.
Bidirectional drug interactions
Atazanavir
Clarithromycin and atazanavir are both substrates and inhibitors of the CYP3A isoenzyme. There is evidence of a bidirectional interaction between these drugs. Coadministration of clarithromycin (500 mg twice daily) and atazanavir (400 mg once daily) may result in a twofold increase in clarithromycin exposure and a 70% decrease in 14-OH-clarithromycin exposure, with a 28% increase in atazanavir AUC. Due to the wide therapeutic range of clarithromycin, dose reduction is not required in patients with normal renal function. In patients with moderate renal failure (creatinine clearance 30 - 60 ml/min), the dose of clarithromycin should be reduced by 50%. In patients with creatinine clearance less than 30 ml/min, the dose of clarithromycin should be reduced by 75% using the appropriate clarithromycin dosage form. Clarithromycin in doses exceeding 1000 mg per day should not be used in conjunction with protease inhibitors.
Blockers of "slow" calcium channels
When using clarithromycin simultaneously with blockers of “slow” calcium channels 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 slow calcium channel blockers, may increase with simultaneous use. Arterial hypotension, bradyarrhythmia and lactic acidosis are possible when taking clarithromycin and verapamil simultaneously.
Itraconazole
Clarithromycin and itraconazole are substrates and inhibitors of the CYP3A isoenzyme, which determines the bidirectional interaction of the drugs. Clarithromycin may increase plasma concentrations of itraconazole, while itraconazole may increase plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be closely monitored for symptoms of increased or prolonged pharmacological effects of these drugs.
Saquinavir
Clarithromycin and saquinavir are CYP3A substrates and inhibitors, resulting in a bidirectional drug interaction. Coadministration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily) in 12 healthy volunteers increased the AUC and Cmax of saquinavir by 177% and 187%, respectively, compared with saquinavir. separately. The AUC and Cmax values of clarithromycin were approximately 40% higher than with clarithromycin monotherapy. When these two drugs are used together for a limited time at the doses/dosage forms indicated above, no dose adjustment is required. Results from drug interaction studies using saquinavir soft gelatin capsules may not be consistent with the effects observed with saquinavir hard gelatin capsules. The results of drug interaction studies with saquinavir monotherapy may not be consistent with the effects observed with saquinavir hard gelatin capsules. The results of drug interaction studies with saquinavir monotherapy may not be consistent with the effects observed with saquinavir/ritonavir therapy. When taking saquinavir with ritonavir, consider the potential effect of ritonavir on clarithromycin.
Side effects
The most common side effects from the gastrointestinal tract are nausea, vomiting, epigastric discomfort, colic, soft and dark stools, and diarrhea. If severe and persistent diarrhea occurs, pseudomembranous colitis should be suspected. Other common side effects include decreased sense of smell or taste. Sometimes hypersensitivity reactions may occur.
Rare side effects include short-term cholestasis and jaundice. In critically ill patients with relevant comorbidities, the risk of death may increase. Also a rare side effect is a change in myocardial excitability, which is manifested on the ECG by an increase in the QT interval and tachycardia. This fact increases the risk of life-threatening arrhythmias.
Side effects related to the central nervous system are rare. These include dizziness, headache, anxiety, drowsiness, hallucinations, nightmares, and psychosis. Also rare are inflammation and discoloration of the tongue, inflammation of the gums and/or oral mucosa, fungal infections of the mucous membranes, and tooth discoloration. Tooth discoloration can be eliminated by cleaning.
Very rare: pancreatitis, interstitial nephritis, leukopenia, thrombocytopenia.
Clarithromycinum
From the gastrointestinal tract:
often - diarrhea, vomiting, dyspepsia, nausea, abdominal pain; uncommon - esophagitis, gastroesophageal reflux disease, gastritis, proctalgia, stomatitis, glossitis, bloating, constipation, dry mouth, belching, flatulence, increased concentration of bilirubin in the blood, increased activity of ALT, AST, gamma-glutamyltransferase, alkaline phosphatase, lactate dehydrogenase, cholestasis, hepatitis, including cholestatic and hepatocellular; frequency unknown - acute pancreatitis, discoloration of the tongue and teeth, liver failure, cholestatic jaundice.
Allergic reactions:
often - rash; uncommon - anaphylactoid reaction, hypersensitivity, bullous dermatitis, itching, urticaria, maculopapular rash; frequency unknown - anaphylactic reaction, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome).
From the side of the central nervous system:
often - headache, insomnia; uncommon - loss of consciousness, dyskinesia, dizziness, drowsiness, tremor, anxiety, increased excitability; frequency unknown - convulsions, psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, nightmares, paresthesia, mania.
From the skin:
often - intense sweating; frequency unknown - acne, hemorrhages.
From the senses:
often - violation, perversion of taste; infrequently - vertigo, hearing loss, ringing in the ears.
From the heart and blood vessels:
often - vasodilation; uncommon - cardiac arrest, atrial fibrillation, prolongation of the QT interval on the ECG, extrasystole, atrial flutter.
From the urinary system
: uncommon - increased creatinine concentration, change in urine color.
Metabolism and nutrition:
uncommon - anorexia, decreased appetite, increased urea concentration, change in albumin-globulin ratio.
From the musculoskeletal system:
uncommon - muscle spasm, musculoskeletal stiffness, myalgia; when used while taking statins, it often results in rhabdomyolysis and myopathy.
From the respiratory system:
Uncommon: asthma, nosebleeds, pulmonary embolism.
From the hematopoietic system:
uncommon - leukopenia, neutropenia, eosinophilia, thrombocythemia.
From the blood coagulation system:
infrequently - an increase in the value of the international normalized ratio, prolongation of prothrombin time.
Infectious and parasitic diseases:
infrequently - cellulitis, candidiasis, gastroenteritis, secondary infections (including vaginal).
Local reactions:
very often - phlebitis at the injection site, often - pain at the injection site, inflammation at the injection site.
From the body as a whole:
uncommon - malaise, hyperthermia, asthenia, chest pain, chills, fatigue.
Clarithromycin recipe in Latin
The Latin prescription for clarithromycin is prescribed in the form of tablets with a dosage of 250 and 500 mg; in the form of extended-release (ER) tablets 500 mg; in the form of a suspension for oral administration 125 or 250 mg/5 ml; in bottles in powder form 500 mg.
Read the general rules for writing a prescription in Latin here.
For example, let's prescribe clarithromycin at a dosage of 250 mg in tablet form - read more about the recipe for tablets in Latin.
Rp.: Clarithromycini 250 mg Dtd N 14 in tab. S. Orally, 1 tablet 2 times a day.
We will also write out a prescription for clarithromycin in Latin in the form of a suspension with a dosage of 250 mg/5 ml - more details about the recipe for the suspension in Latin. Since the suspensions are produced in bottles, there is no need to indicate them - for more details, see the recipe for the bottles in Latin.
Rp.: Susp. Clarithromycini 250 mg/5 ml Dtd N 10 S. Orally, 1 suspension 2 times a day.
The recipe for clarithromycin in Latin in powder form, more details about the recipe for powder in Latin, will look like this:
Rp.: Pulv. Clarithromycini 0.5 Dtd N 12 S. Dilute with saline. solution, intramuscularly 1 time per day.
Introduction
The medical problem of improving the quality of life in infectious diseases of the respiratory system, based on effective and safe therapy in outpatient and inpatient settings, does not lose its relevance due to the continued high incidence, the growth of the older population, and the changing level of resistance of the main pathogens.
The multifaceted etiopathogenetic effect of the macrolide antibiotic clarithromycin on the process of bacterial inflammation ensures its high effectiveness against respiratory tract infections. The antimicrobial spectrum, including S. pneumoniae, intracellular microorganisms, H. influenzae, which are key pathogens in both community-acquired pneumonia (CAP) and exacerbation of chronic obstructive pulmonary disease (COPD), unique non-antibacterial properties, new prolonged forms of clarithromycin determine its relevance in therapy. Ongoing clinical studies make it possible to expand the range of targets for clarithromycin in modern pulmonology. In the presence of atypical mycobacteria, Pseudomonas aeruginosa, clarithromycin is used in combination with other antimicrobial drugs, significantly increasing the effectiveness of therapy [1–3]. The non-antimicrobial effects of clarithromycin - anti-inflammatory, immunomodulatory, mucolytic - have been studied in diffuse panbronchiolitis, bronchial asthma, and cystic fibrosis [4].
Clinical and pharmacological characteristics of clarithromycin
The synthesis of clarithromycin was carried out by including a methoxy group at the position of the 6th macrocyclic lactone ring in the structure of erythromycin. This contributed to increased acid stability and improved pharmacodynamic and pharmacokinetic properties. The drug has been used in clinical practice since 1991.
The mechanism of the antimicrobial action of clarithromycin is due to a violation of protein synthesis in the microbial cell. As a result of reversible binding to the 50S ribosomal subunit and inhibition of translocation and transpeptidation reactions, the formation and growth of the peptide chain is inhibited [4]. The main effect of clarithromycin is bacteriostatic, but at high concentrations and low microbial density the drug has a bactericidal effect against S. pyogenes and S. pneumoniae. Moreover, the antimicrobial activity against these pathogens and methicillin-sensitive strains of S. aureus is 2–4 times higher than that of erythromycin [4] (Table 1).
Higher activity of clarithromycin compared to erythromycin is observed against L. pneumophila, C. trachomatis and Ureaplasma urealyticum; it is comparable to erythromycin against M. pneumoniae and C. pneumoniae. Under in vivo conditions, the synergistic effect of clarithromycin and its active metabolite 14-hydroxyclarithromycin (14-HCM) provides high activity against H. influenzae [5]. Clarithromycin exhibits clinically significant activity against Bordetella pertussis, Campylobacter jejuni, Moraxella catarrhalis, M. avium and Toxoplasma gondii [3, 4]. Over the past 20 years, infectious lung diseases caused by non-tuberculous mycobacteria, the so-called. Mycobacterium avium-intracellulare complex (MAC) has become a serious problem in pulmonology [6]. Therefore, assessing the effectiveness of clarithromycin against MAC is clinically relevant. Gram-negative bacteria of the family Enterobacteriaceae and non-fermenting microorganisms are naturally resistant to clarithromycin. At the same time, the ability of the latter to inhibit the production of biofilms and the motility of P. aeruginosa, thereby reducing the adhesion and degree of colonization of the surface of the pulmonary epithelium, assigns it an adjuvant role in combination with antipseudomonas cephalosporins [7].
Clarithromycin is rapidly absorbed from the gastrointestinal (GIT) tract, with peak plasma concentrations in adults reaching 1.8–3.3 hours depending on the dosage form (tablets or suspension) [8]. Bioavailability is 52–55%, increasing slightly when taken simultaneously with food and in elderly patients [5].
The peculiarity of the sustained-release dosage form (Klacid SR) is that peak concentration in the blood is reached more slowly at a lower level [5, 8]. There are no significant differences in the area under the pharmacokinetic curve for the immediate and sustained release forms. The distribution of clarithromycin and 14-GCM is characterized by high and stable concentrations in sputum, lung tissue, and accumulation in polymorphonuclear neutrophils, macrophages, and monocytes [3–5]. The creation of high tissue concentrations is also typical for a sustained-release dosage form [8]. The metabolism of clarithromycin occurs in the liver with the participation of the cytochrome P450 system. Excretion is carried out by the kidneys in unchanged form (20–30%) and in the form of metabolites (10–15%). The half-life when taken at a dose of 250 mg 2 times a day is 3-4 hours and increases to 7-8 hours when the dose is increased to 500 mg 2 times a day.
The effectiveness of clarithromycin in the treatment of respiratory system infections is ensured by its concentrations in the fluid lining the alveoli, hundreds of times, and in alveolar macrophages thousands of times higher than those in the blood serum [9, 10]. In vitro studies have shown that the concentrations of clarithromycin in lung tissue, in contrast to those of azithromycin, amoxicillin/clavulanate and levofloxacin, limit the development of resistance in S. pneumoniae [11].
In terms of the spectrum of adverse reactions, clarithromycin is similar to erythromycin, but they occur much less frequently, are less pronounced, are transient in nature, and more rarely require drug discontinuation or medication adjustment. The most common reactions are from the gastrointestinal tract (diarrhea, nausea, change in taste) - up to 3% in adults; in children, diarrhea, vomiting, abdominal pain and headache were observed in 6.6; 6.3; 2.4 and 1.6% of cases, respectively. Klacid SR is better tolerated compared to the conventional form [12].
The potential for drug interactions due to inhibition of cytochrome P450 is generally lower with clarithromycin compared to erythromycin. When combined with warfarin, cyclosporine, digoxin, carbamazepine, their concentrations in the blood may increase.
Etiology of lower respiratory tract infections
The etiological structure of CAP is dominated by S. pneumoniae (30–60%). H. influenzae ranks second (5–18%), and is more often detected in young children and people over 65 years of age, smokers and COPD [13]. During exacerbation of COPD, pneumococcus and Haemophilus influenzae change places in importance. H. influenzae colonizes in the upper respiratory tract in 5–20% of patients of different age groups, so identifying the pathogen as significant in each episode of exacerbation of COPD and CAP can be difficult. An important place is occupied by intracellular pathogens M. pneumoniae, C. pneumoniae and L. pneumoniae.
M. pneumoniae occurs in 10–20% of cases of CAP, more often in young people; the outcome of the disease is usually favorable, and mortality is low. The pathogen is a membrane parasite capable of long-term persistence; the absence of a cell wall determines resistance to b-lactams, and the three-layer cytoplasmic membrane plays an important role in the adsorption of mycoplasmas to the surface structures of host cells (erythrocytes, cells of the ciliated epithelium of the bronchi, etc.).
C. pneumoniae causes 5–15% of CAP in adults; during epidemiological outbreaks in isolated and semi-isolated groups, this figure can increase to 25%, mortality is 9.8% [14, 15]. The pathogen has tropism for bronchial columnar epithelial cells, alveolar macrophages, monocytes, and vascular endothelial cells.
L. pneumophila causes 2–6% of the total number of CAPs and accounts for 10–15% of atypical pathogens. In the human body, Legionella multiply mainly in alveolar macrophages (less often in polymorphonuclear neutrophils and monocytes), destroy them and enter the lung tissue. As a result of repeated cycles, a large number of bacteria accumulate, causing the development of an acute process. Legionella pneumonia is quite severe, accounting for up to 8% of patients hospitalized in the ICU, and is characterized by high mortality [15].
M. catarrhalis is a rare pathogen of CAP (up to 1%), however, the true role of this pathogen is difficult to assess, since it disguises itself as saprophytic neisseria and it is not always possible to identify it.
Even more rare pathogens of both CAP and exacerbation of COPD include S. aureus, Klebsiella pneumoniae, and other enterobacteria. In very rare cases, CAP and exacerbation of COPD can be caused by P. aeruginosa (in patients with cystic fibrosis, in the presence of bronchiectasis). A mixed infection is often observed. The etiological structure of CAP may vary depending on the age of the patients, the severity of the disease, and the presence of concomitant pathology. From a practical point of view, it is advisable to distinguish groups of patients with CAP, taking into account age, concomitant pathology and severity of the disease. There may be differences between these groups not only in etiology, but also in prognosis (Table 2).
The main antimicrobial drugs recommended for the treatment of CAP in foreign and domestic guidelines are b-lactams (aminopenicillins, cephalosporins of II–III generations), macrolides and respiratory fluoroquinolones.
High concentrations of clarithromycin in lung tissue, good tolerability, comparable effectiveness of prolonged and standard forms, as well as the results of numerous clinical studies determine the priority of this antibiotic among other “respiratory” drugs.
Preference for macrolides, namely clarithromycin, in outpatient treatment of CAP in young patients without concomitant chronic diseases and risk factors is given in modern international and domestic recommendations [16–18]. Clarithromycin, along with erythromycin and azithromycin, is the drug of choice for etiotropic treatment of CAP caused by C. pneumoniae, L. pneumophila and M. pneumoniae, as well as in case of ineffective initial therapy with b-lactams. The microbiological activity of clarithromycin against S. pneumoniae and S. pyogenes is the highest among macrolides; it has the greatest effect against S. aureus, has advantages over L. pneumophila in terms of activity, and ranks among the first among macrolides in terms of activity against chlamydia inside lymphocytes. The in vitro activity of clarithromycin against H. influenzae is lower than that of azithromycin, but in vivo the actual antihemophilic effect increases significantly due to the synergism of clarithromycin and its active metabolite
14-GKM. A similar increase in the activity of clarithromycin metabolite is observed in relation to pneumococci, including those resistant to penicillin and erythromycin.
In hospitalized patients, macrolides are used in combination with b-lactams, especially in severe cases. This combination has been shown to improve treatment outcome and reduce the length of patient stay in hospital [19–21].
The presence of a parenteral dosage form of clarithromycin allows its use in the form of step-down therapy; its tolerability is better than erythromycin, the frequency of administration is less.
Resistance mechanisms of key pathogens
Acquired resistance of microorganisms to macrolides can be due to several mechanisms: modification of the target of action, active removal of the antibiotic from the microbial cell (efflux), enzymatic inactivation.
Methylation of ribosomes is the main and most studied mechanism of target modification. It is characteristic of Streptococcus spp., Staphylococcus spp., Campylobacter spp. and is due to the presence in these bacteria of special genes - erm (erythromycin ribosome methylase), responsible for the synthesis of protein methylases, as a result of which the binding of the macrolide to the target of action is disrupted [3]. In this case, cross-resistance (the so-called MLS-type resistance) to macrolides, lincosamides and streptogramin B is formed.
Mutations in rRNA and ribosomal proteins L4, L16, L22 are a mechanism of resistance, the clinical significance of which has not yet been determined. Single mutations in the V domain of rRNA are observed in S. pneumoniae, Mycobacterium spp., H. pylori, B. pertussis; they lead to the expression of MLSb and ML resistance phenotypes (resistance to macrolides and lincosamides). Mutations in L proteins found in clinical strains of S. pneumoniae and S. pyogenes confer resistance to erythromycin while maintaining sensitivity to lincosamides [22].
Active removal (efflux) from a microbial cell is carried out with the participation of a proton pump encoded by the mefA and mefE genes [23]. In this case, only 14- and 15-membered macrolides are excreted; sensitivity to 16-membered macrolides, lincosamides and streptogramin B is maintained. This type of resistance is characterized by fairly low values of the minimum inhibitory concentration (MIC) of erythromycin and clarithromycin (4–32 mg/l).
Enzymatic inactivation in the mechanism of formation of resistance to clarithromycin has no clinical significance.
The most significant problem in the treatment of CAP and exacerbation of COPD is the growing resistance of one of the main pathogens - S. pneumoniae. In the multicenter epidemiological study GRASP, among 2487 clinical strains of S. pneumoniae from Europe, East Asia and North Africa, from 4.0 to 66.1% were resistant to erythromycin [24]. In the United States, from 1992 to 2001, the prevalence of pneumococcal resistance to erythromycin increased 4.5 times. In Russia, the resistance of S. pneumoniae to macrolides remains low compared to other countries. According to the multicenter study PeGAS-II, the frequency of detection of clinical strains not sensitive to clarithromycin was in 2003–2005. 6.4% [25]. However, in vitro data on clarithromycin resistance in S. pneumoniae based on serum MIC levels do not fully reflect clinical results. This paradox of clarithromycin is explained by the fact that the drug is well distributed in various organs and tissues and its concentrations in lung tissue and bronchial secretions significantly exceed serum levels. Therefore, the pharmacodynamic condition for effectiveness (concentration above the MIC at the site of infection for more than 40% of the dosing interval) occurs for a significantly larger number of S. pneumoniae strains, including those resistant in vitro with low MIC values (‡ 8 μg/ml), which is a predictor of clinical response to treatment.
Clarithromycin for CAP and exacerbation of COPD
Many clinical studies and as a result of many years of experience in use have revealed the high effectiveness of clarithromycin in the treatment of lower respiratory tract infections.
According to the results of a study that included 252 patients with CAP, a 7-day course of treatment with extended-release clarithromycin (1000 mg once daily) was as clinically effective as a similar duration of treatment with levofloxacin (500 mg once daily). The overall rates of pathogen eradication (87% and 88%) and radiographic improvement (95% and 88%) also did not differ. Both drugs turned out to be equally effective against both typical and atypical pathogens [26].
In severe cases of CAP in a hospital setting, combination therapy is more effective. This has been confirmed by many clinical observations. A cohort study involving 1391 patients with CAP found that mortality during treatment with a combination of a third-generation cephalosporin with a macrolide was 2 times lower than with monotherapy
b-lactam [19]. Another study showed that the combination of a b-lactam with a macrolide is more effective than that of a b-lactam with a fluoroquinolone (mortality rate - 4.9 and 15.0%, respectively) [20, 21].
Exacerbation of COPD as a basis for prescribing antibiotic therapy is characterized by increased shortness of breath, an increase in the volume of sputum discharge and an increase in the amount of pus in it. Good penetration of clarithromycin into bronchial secretions and a beneficial effect on mucociliary clearance are important factors for its high effectiveness in treating exacerbations of this disease. According to modern recommendations, clarithromycin is considered as an alternative drug for exacerbation of COPD in young patients without significant concomitant diseases and severe bronchial obstruction [27].
According to randomized trials, long-acting clarithromycin is as effective as the standard drug in treating patients with exacerbation of COPD. In most clinical studies, clarithromycin was not inferior in effectiveness to b-lactams and fluoroquinolones traditionally used for exacerbation of COPD, while its clinical effectiveness was 82–98, microbiological – 58–98% [28–31]. The clinical and microbiological efficacy of immediate- and sustained-release dosage forms in patients with exacerbation of COPD was comparable to that of amoxicillin/clavulanate. However, patients receiving extended-release clarithromycin were more likely to report a decrease or cessation of purulent sputum production compared with those receiving immediate-release clarithromycin (96% vs. 85%; P = 0.028) or amoxicillin/clavulanate (85% vs. 75%; P = 0.045). [32–35].
Non-antimicrobial effects of clarithromycin
Regardless of the antimicrobial effect, clarithromycin, like a number of other macrolides, exhibits anti-inflammatory, immunomodulatory and mucoregulatory effects at the level of the respiratory system.
Clarithromycin has a modulating effect on phagocytosis, chemotaxis, killing and apoptosis of neutrophils. The oxidative “explosion” is inhibited, resulting in a decrease in the formation of highly active compounds that can damage one’s own tissues. The synthesis and/or secretion of pro-inflammatory cytokines (interleukins-1, -6, -8, tumor necrosis factor a) is inhibited and the secretion of anti-inflammatory cytokines (interleukins-2, -4, -10) is enhanced [36, 37].
The revealed ability of clarithromycin to reduce bronchial hyperreactivity has a beneficial effect on the clearance of bronchial and nasal secretions. At the same time, sputum production decreases in patients with excessive secretion, for example, with diffuse panbronchiolitis [38]. Clarithromycin is also able to prevent the adhesion of certain gram-negative bacteria to the surface of the host cells. The non-antimicrobial efficacy of clarithromycin has been intensively studied in vitro and in vivo.
Thus, a 4-year intake of clarithromycin at a dose of 200 mg/day by patients with diffuse panbronchiolitis significantly improved clinical symptoms and functional indicators by the 6th month of treatment with further positive dynamics throughout the entire period of therapy. A number of studies have demonstrated the effectiveness of clarithromycin in bronchial asthma, noting a significant reduction in the severity of clinical symptoms, the number of eosinophils in the blood and sputum, as well as a decrease in bronchial hyperresponsiveness compared to placebo. In a study by Nixon L. et al. demonstrated the ability of clarithromycin prescribed to 25 patients with COPD for 2 weeks at a dose of 500 mg 2 times a day to improve pulmonary function parameters and reduce the severity of clinical symptoms [39]. In a study of a sustained-release dosage form taken for 7 days by 120 patients with COPD without an exacerbation, a significant decrease in the content of interleukin-8 in sputum and a decrease in its viscosity were noted [40].
Thus, the presence of additional properties, along with high antibacterial activity, ensures rapid regression of symptoms and improvement in the condition of patients when treated with clarithromycin for respiratory tract infections.
Conclusion
Clarithromycin has rightfully occupied its niche in the treatment of acute and chronic respiratory tract infections. It retains one of the leading positions in outpatient practice and in the pharmaceutical market of the Russian Federation, which is due to its wide spectrum of activity, rapid achievement of high peak concentrations at the site of infection and a favorable safety profile. A dosage form with a delayed release of the active substance due to a special surface layer and matrix base (Abbott's Klacid SR) is identical in effectiveness to the standard one, is better tolerated, improves compliance and can be recommended for active use. The evidence available today on non-antibacterial action, combined with the favorable clinical and pharmacological characteristics of clarithromycin, allows us to consider it as an adjuvant drug in the treatment of many respiratory diseases.
