Antibiotics (Properties, Application, Interactions) - Posokhova K.A., Viktorov O.P. 2005

Macrolides, Azalides, Ketolides, Streptogramins, Pristinamycins
Macrolides and Azalides

A separate subgroup is formed by azalides (which feature a nitrogen atom incorporated into the lactone ring), represented by azithromycin, which differs from other macrolides in its pharmacokinetic profile and spectrum of antimicrobial activity.

Based on the number of carbon atoms in the lactone ring, macrolides are conventionally divided into the following groups:

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MECHANISM OF ACTION. Macrolides exhibit bacteriostatic activity by binding to the catalytic peptidyl transferase center of the 50S ribosomal subunit. This prevents the Transfer RNA-amino acid complex from accessing the Messenger RNA-ribosome complex, thereby disrupting the formation and elongation of the peptide chain, which inhibits Protein Synthesis in microbial Cells. Against certain microorganisms at high concentrations, macrolides act bactericidally.

The antibacterial spectrum of macrolides covers staphylococci, streptococci, gonococci, anaerobic cocci, enterobacteria, Pseudomonas strains, H. influenzae, intracellular pathogens (Campylobacter, Helicobacter, Chlamydia, Legionella, Bordetella, and M. pneumoniae strains), and pathogens that are typically resistant to most Antibiotics (P. carinii, T. gondii, M. avium complex). Unlike other macrolides, azithromycin exhibits significant activity against certain Gram-negative microorganisms, notably Acinetobacter and Pasteurella, and has a more pronounced effect on H. influenzae and M. catarrhalis. Most Gram-negative Bacteria, Fungi, and Viruses are resistant to macrolides.

Spiramycin outperforms other macrolides against penicillin-resistant viridans streptococci (particularly S. mitis), T. gondii, and Cryptosporidium spp. High sensitivity to spiramycin and erythromycin is exhibited by certain oral anaerobes (Peptostreptococcus spp., Peptococcus spp., Bacteroides spp.). Clarithromycin demonstrates higher activity than other macrolides and azithromycin against M. avium complex (a frequent opportunistic pathogen in AIDS patients) and M. leprae.

Summary data on microbial susceptibility to macrolides are presented in Table 19.

Table 19. Susceptibility of microorganisms to macrolides (V.P. Yakovlev, V.S. Yakovlev, 2003)

Notes: ¹ penicillin-susceptible; ² penicillin-resistant, susceptibility to macrolides varies, highest to telithromycin; ³ clarithromycin, azithromycin, roxithromycin, erythromycin.

Of the 6 currently known Mechanisms of microbial resistance to macrolides, azalides, and Streptogramins, The most significant are enzymatic inactivation (via phosphorylation of sugar hydroxyl groups), ribosomal methylation, and active efflux from the bacterial Cell. The rate at which resistance to macrolides develops during clinical use does not differ significantly from other antibiotic classes. Microorganisms exhibit cross-resistance to drugs within this group.

Pharmacokinetics. Macrolides are rapidly absorbed from the gastrointestinal tract, with the exception of erythromycin, which has low oral bioavailability. This is due to incomplete absorption from the GI tract caused by degradation by gastric acid (tablets are enteric-coated to prevent this) and a strong stimulatory effect on motilin receptors, leading to enhanced peristalsis. Newer macrolides are more completely absorbed from the GI tract due to greater acid stability. Food intake affects the absorption of certain macrolides: the absorption of erythromycin base and spiramycin is significantly inhibited, midecamycin absorption is mildly affected, while the bioavailability of clarithromycin, josamycin, miocamycin, and telithromycin remains unaffected. Azithromycin absorption may be delayed by calcium- and aluminum-containing antacids.

The pharmacokinetics of macrolides largely depend on environmental pH. As the pH drops, drug ionization increases, converting them into inactive forms. The optimal pH level for erythromycin, clarithromycin, and azithromycin is above 7.5.

Macrolides are rapidly and widely distributed into Tissues. Their highest accumulation is observed in lung tissue, bronchial secretions, saliva, Tonsils, Middle ear, Paranasal Sinuses, gastrointestinal mucosa, prostate tissue, eyes, Skin, Bile, Urethra, Uterus and its appendages, and the Placenta. They do not cross the Blood-Brain barrier, even in cases of meningitis. Macrolides are eliminated slowly from tissues, where they tend to accumulate and maintain effective concentrations for extended periods. The tissue-to-blood concentration ratio is (5–10):1 for erythromycin and (100–500):1 for azithromycin. Of great importance is the ability of macrolides to penetrate phagocytic cells (via Active Transport) and achieve concentrations 13–20 times higher than those in extracellular fluid. This facilitates the eradication of intracellular Staphylococcus aureus, Legionella, Chlamydia, and Listeria. Antibiotics that fail to penetrate polymorphonuclear leukocytes or alveolar macrophages lack this capability, allowing microorganisms surviving within phagocytes to eventually re-enter the blood and tissues, leading to disease relapse. This property explains the phenomenon known as the "macrolide paradox" (where minimum inhibitory concentration [MIC] values for these drugs are significantly higher than the concentrations they achieve in the blood of treated patients).

Furthermore, azithromycin—which has relatively low oral bioavailability (due to presystemic elimination) and does not yield high blood concentrations—is transported by macrophages to the site of inflammation, where it accumulates in high concentrations and is subsequently released in response to bacterial stimuli.

The active tissue concentration of macrolides persists for 10–18 hours after cessation of therapy for erythromycin, 2–3 days for spiramycin, and 3–4 days for azithromycin.

Macrolides are metabolized in the Liver by the microsomal enzyme system. Based on their affinity for cytochrome P-450 Enzymes, macrolides can be divided into three groups: highest affinity is seen in erythromycin and oleandomycin; moderate affinity in clarithromycin, midecamycin, josamycin, and roxithromycin; while dirithromycin, spiramycin, and azithromycin show no such interaction. Macrolides are excreted primarily via bile and to a lesser extent unchanged in urine, achieving high concentrations in both. Enterohepatic Circulation is characteristic. Erythromycin and oleandomycin induce hepatic microsomal enzymes, which accelerates their own METABOLISM into compounds that inactivate cytochrome P-450. This disrupts the biotransformation of other drugs co-administered with these macrolides (theophylline, ergot Alkaloids, bromocriptine, carbamazepine, etc.) and creates conditions for toxic manifestations.

In renal failure, the elimination of clarithromycin and roxithromycin may be significantly delayed: if creatinine clearance is < 30 mL/min, their dose should be halved or the dosing interval extended.

Indications for macrolides and azalides: upper and Lower Respiratory Tract infections (acute Bronchitis, acute Exacerbation of chronic bronchitis, community-acquired Pneumonia); ENT infections (otitis media, unless caused by H. influenzae, acute streptococcal tonsillitis, sinusitis, pharyngitis); gynecological infections; pelvic inflammatory disease; uncomplicated skin and soft tissue Infections caused by staphylococci or streptococci (Pyoderma, furuncles, wound infections, etc.); Toxoplasmosis in pregnant women and newborns; atypical mycobacterioses in HIV-infected individuals; ophthalmological infections, including trachoma; pertussis, diphtheria, leprosy, and cystic fibrosis.

Macrolides are the drugs of choice for Mycoplasma and Chlamydia pneumonia in newborns and older children. They are indicated for young children with chronic respiratory infections caused by Ureaplasma urealyticum, acquired prenatally or during childbirth. Up to 87% of U. urealyticum strains are resistant to erythromycin but remain susceptible to clarithromycin and azithromycin.

Macrolides are first-line drugs (in combination with rifampicin) for treating legionellosis (Legionnaires' disease). The Use of macrolides for community-acquired pneumonia is justified by their broad spectrum of activity, including efficacy against atypical pathogens. However, their activity against S. pneumoniae and H. influenzae is inferior to that of beta-lactam antibiotics. Clarithromycin and azithromycin exhibit sufficient bactericidal activity against these pathogens, including beta-lactamase-producing strains of H. influenzae. Because these two antibiotics are available in both oral and intravenous formulations, they are well-suited for sequential ("step-down") therapy.

Roxithromycin, clarithromycin, and azithromycin are highly effective in treating acute exacerbations of Chronic bronchitis.

Treatment of diphtheria (including in asymptomatic carriers) and pertussis should be initiated with macrolides or Tetracyclines. In cases of diphtheria, the concurrent administration of specific antitoxins is mandatory.

Clarithromycin and azithromycin are used as anti-Helicobacter agents in PEPTIC ULCER DISEASE of The Stomach and duodenum. The most effective regimens combine them with amoxicillin (or imidazoles) and omeprazole (or other H⁺, K⁺-ATPase inhibitors). Such treatment regimens achieve H. pylori eradication in over 90% of cases. The Role of macrolides in managing Helicobacter-associated pathologies has grown significantly due to the spread of metronidazole resistance (exceeding 50% in many regions). In Campylobacter-induced gastroenteritis, macrolides help eliminate the microorganisms from stool, although they do not always shorten the duration of clinical symptoms.

Erythromycin is prescribed 4 times daily for 10–15 days. Modern macrolides, due to their prolonged action, can be administered twice daily (azithromycin once daily) with a shorter course of therapy. The duration of azithromycin treatment can range from 1 to 3 to 5 days, depending on the disease entity. Even in pneumonia, azithromycin can be used for 3–5 days thanks to high antibiotic concentrations in alveolar macrophages and its sustained release from them for 72–96 hours (up to 7 days) after treatment cessation. In terms of efficacy, a 3-day course of azithromycin for lower respiratory tract infections is equivalent to a 10-day course of other oral antibiotics. It is also the drug of choice for treating pneumonias caused by atypical pathogens in pediatric practice (over 30% of lower respiratory tract infections in children are associated with M. pneumoniae and nearly 15% with C. pneumoniae).

Semisynthetic macrolides are highly effective against non-gonococcal urogenital infections, particularly those caused by C. trachomatis, M. hominis, and U. urealyticum; in addition, azithromycin is also effective against Gonorrhea. The efficacy of the latter is evident even with a single 1.0 g dose. Roxithromycin is prescribed for non-gonococcal genital infections at 300 mg daily for 10 days. Spiramycin (rovamycin) is administered in a daily divided dose of 6-9 million IU (in 2-3 intakes) for gynecological conditions, prostatitis, urethritis of various etiologies, Sexually Transmitted Infections—specifically genital and Extragenital Chlamydiosis—and toxoplasmosis (including in pregnant women). Erythromycin serves as an alternative treatment for Syphilis in patients with penicillin intolerance.

A 100% clinical and bacteriological efficacy has been observed with azithromycin in typhoid fever patients (500 mg daily for 7 days). Given the significant toxicity of chloramphenicol, which is traditionally considered the drug of choice for this condition, the high susceptibility of Salmonella typhi to azithromycin establishes it as a first-line agent for typhoid fever treatment.

Macrolides are highly active against zoonotic infections, including Q fever, Mediterranean spotted fever (and other rickettsioses), cat-scratch disease (caused by B. henselae), and others.

Adverse effects. Macrolides are among the least toxic antibiotics. Nevertheless, they may cause dyspeptic symptoms such as nausea, vomiting, and diarrhea. Newer macrolides have a minimal impact on colonization resistance and do not provoke severe dysbiosis, which is frequently observed with other antimicrobial treatments, particularly broad-spectrum antibiotics. Azithromycin is the best-tolerated agent, largely due to its short treatment courses.

Cross-allergic reactions are characteristic of all macrolides. An allergic reaction triggered by azithromycin may recur 3-4 weeks after the cessation of symptomatic treatment, primarily due to the slow elimination of the drug from tissues.

Macrolides stimulate gastrointestinal motilin receptors, leading to enhanced peristalsis and diarrhea. This effect is most pronounced with erythromycin and to a lesser extent with spiramycin and midecamycin. Azithromycin exhibits no effect on gastrointestinal motility.

Macrolides (erythromycin, oleandomycin, josamycin, clarithromycin, spiramycin) can induce cholestasis and even acute cholestatic hepatitis. Liver injury is most commonly associated with erythromycin estolate (not utilized in our country) and is linked to The formation of hepatotoxic nitrosoalkane compounds during erythromycin biotransformation. Other macrolides are metabolized via alternative pathways and thus exert no adverse effects on the liver.

Co-administration of macrolides (erythromycin, oleandomycin) with theophylline, ergot alkaloids, bromocriptine, or carbamazepine inhibits the metabolism of the latter, potentially leading to toxic manifestations such as cardiovascular and Central Nervous system disturbances, as well as ergotism (with extremity necrosis). Based on the degree of microsomal enzyme system inhibition, macrolides can be ranked in the following order: erythromycin = oleandomycin > clarithromycin > roxithromycin > azithromycin > spiramycin.

Macrolide therapy may result in reversible Hearing loss.

High-dose administration of erythromycin, spiramycin, or telithromycin may lead to PQ interval prolongation and Cardiac Arrhythmias, specifically ventricular tachycardia (torsades de pointes).

Subinhibitory concentrations of erythromycin promote β-lactamase production and The Development of microbial resistance not only to erythromycin itself but also to other macrolides and Lincosamides. This resistance is associated with plasmid activity in staphylococci and streptococci and can be transmitted between different species. Plasmid-mediated resistance to erythromycin and clindamycin can be transferred to Bacteroides fragilis (B. fragilis) and Clostridioides difficile (C. difficile). Therefore, macrolides, particularly erythromycin, must be administered at doses that ensure effective antibiotic concentrations in Body Fluids and tissues.

Interactions. The combined use of macrolides with beta-lactam antibiotics, Aminoglycosides, rifampin, and fluoroquinolones produces a synergistic effect. In such cases, macrolides are typically incorporated into combination regimens to target atypical pathogens.

Macrolides may diminish the bactericidal efficacy of Penicillins in meningitis and Sepsis; consequently, concurrent administration in such cases is best avoided. Rifampin, when used alongside clarithromycin to treat infections caused by Mycobacterium spp. or Legionella spp., accelerates the metabolism and reduces the serum concentration of the latter. Concomitant use of macrolides with chloramphenicol and lincosamides (due to identical antimicrobial mechanisms), or with astemizole and terfenadine (which also exhibit arrhythmogenic potential), is unfavorable. As noted above, serious consequences can arise from combining macrolides with drugs that have a narrow therapeutic index and are metabolized by the cytochrome P450 system (specifically the CYP3A4 isoform). Such agents include carbamazepine, cyclosporine, xanthines, valproic acid, indirect anticoagulants, cisapride, and others.

Clarithromycin is contraindicated during Pregnancy. Erythromycin, josamycin, and spiramycin may be used in pregnant women, whereas azithromycin, roxithromycin, and midecamycin should be used with caution.

It is advisable to avoid prescribing azithromycin, clarithromycin, and midecamycin during Lactation, as their safety profile for the nursing infant has not been established.

Unfortunately, the prevalence of macrolide and azalide resistance among microorganisms has currently reached a level that impacts treatment outcomes. One approach to overcoming resistance is the development of novel agents based on the chemical Modification of the erythromycin molecule. Research conducted over the past decade demonstrates the potential inexhaustibility of opportunities for modifying its molecule. The number of synthesized erythromycin derivatives undergoing preclinical evaluation and clinical trials is substantial. Ketolides and anhydrolides are Examples of such emerging agents.