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Macrolides

Macrolides represent a group of antibiotics which consists of macrocyclic lactone ring and different radicals. Depending on the number of carbon atoms in the macrocyclic lactone ring macrolides are divided into 14-, 15-, and 16-membered . The main clinical significance of macrolides consists in affecting gram-positive cocci and intracellular pathogens such as mycoplasma, chlamydia, campylobacter, legionella). Macrolides are the less toxic preparations among other antibacterial drugs.

Classification of macrolides

14-membered 15-membered 16-membered
Natural
  • Erythromycin
  • Oleandomycin
  • Dirithromycin Flurithromycin
  • Ketolide (Telithromycin, Cethromycin)
  • Troleandomycin
  Spiramycin
  • Josamycin
  • Leucomycin
  • Mitomycin
Midecamycin
Half-synthetic
Clarithromycin Azithromycin Midecamycin acetate
Roxithromycin   Rokitamycin

Action mechanism
The antimicrobial effect is associated with suppressing of protein synthesis on ribosomes. Macrolides bind to 50S ribosomal subunits, inhibit the process of peptide chain movement, preventing reactions of translocation and elongation. Macrolides also stimulate the non-specific protective mechanisms exerting intracellular antibacterial effect. Typically, macrolides possess bacteriostatic effect, but in high doses they exert bactericidal effect on beta-hemolytic streptococcus group a, pneumococcus. Along with antibacterial action, macrolides possess immunomodulatory and moderate anti-inflammatory activity.

Spectrum of activity
Macrolides are active against gram-positive cocci, such as S.pyogenes, S.pneumoniae, S.aureus (except MRSA). Unfortunately, more and more microorganisms developed resistance to macrolides for the recent years. However, some 16-membered macrolides in some cases may retain activity against pneumococci and pyogenic streptococci resistant to 14 - and 15-membered products.
Macrolides act on microorganisms that cause whooping cough and diphtheria, Moraxella, Legionella, Campylobacter, Listeria, spirochetes, chlamydia, mycoplasma, ureaplasma, some anaerobes (except for B.fragilis).
Azithromycin is highly effective against H.influenzae, and clarithromycin - against H.pylori and atypical mycobacteria (M.avium). Spiramycin, azithromycin and roxithromycin are active against some protozoa (T.gondii, Cryptosporidium spp.). Enterobacteriaceae, Pseudomonas spp. and Acinetobacter spp. strains have a natural resistance to all macrolides.

Drug indications

  • Infections of upper respiratory system : streptococcal tonsillopharyngitis, acute sinusitis, acute otitis media in children (azithromycin)
  • Lower respiratory tract infections: exacerbation of chronic bronchitis, community-acquired pneumonia (including atypical)
  • Pertussis
  • Diphtheria (erythromycin in combination with diphtheria serum)
  • Infections of skin and soft tissue
  • Sexually transmitted infections: chlamydia, syphilis (excluding neurosyphilis), chancroid, lymphogranuloma venereum
  • Infections of the oral cavity: periodontitis, periostitis
  • Severe acne (erythromycin, azithromycin)
  • Campylobacter gastroenteritis (erythromycin)
  • Eradication of H.pylori in patients with gastric and duodenal ulcer (clarithromycin in combination with amoxicillin, metronidazole and proton pump inhibitors, H2-histamine receptor blockers)
  • Toxoplasmosis (spiramycin)
  • Cryptosporidiosis (spiramycin, roxithromycin)
  • Prevention and treatment of mycobacteriosis caused M.avium in patients with AIDS (clarithromycin, azithromycin)

In prophylaxis:

  • Prevention of whooping cough in humans (erythromycin);
  • Reorganization of meningococcal carriers (spiramycin);
  • All year-round prevention of rheumatism in patients with allergy to penicillin (erythromycin);
  • Prevention of endocarditis in dentistry (azithromycin, clarithromycin);
  • Decontamination of the intestine before surgery on the colon (erythromycin in combination with kanamycin).

Contraindications

  • Allergic reactions to macrolides.
  • Pregnancy (clarithromycin, midecamycin, roxithromycin).
  • Breastfeeding (Josamycin, clarithromycin, midecamycin, roxithromycin, spiramycin).

Cautions

Pregnancy. The most of macrolides (clarithromycin, midecamycin, roxithromycin) are contraindicated for use during pregnancy. Azithromycin can be used only when benefits for mothers overweight potential risk to the fetus
Breastfeeding. Most macrolides penetrate into breast milk and therefore the use of this category of medicines is contraindicated in breastfeeding mothers.
Pediatric use. Macrolides should be used with caution in children under 3 years of age because of high risk of adverse effects.
Geriatric use. Macrolides should be used with caution in elderly patients because of high risk of liver or kidney dysfunction.
Kidney dysfunction. In decreased creatinine clearance lower than 30ml/min half-life period of clarithromycin can be increased up to 20 hours and its active metabolite up to 40 hours. Half-life period of roxithromycin may increase up to 15 hours in patients with decreased creatinine clearance lower than 10ml/min.
Liver dysfunction. Macrolides should be used with caution in patients with severe liver diseases because of high risk of hepatotoxicity (especially for erythromycin and josamycin).
Heart diseases. Macrolides should be used with caution in patients with prolonged QT interval.

Macrolides side effects

  • Gastrointestinal tract: pain or discomfort in the abdomen, nausea, vomiting, diarrhea
  • Liver: transient increase of transaminases, cholestatic hepatitis which can manifest jaundice, fever, general malaise, weakness, abdominal pain, nausea, vomiting (more commom for erythromycin and clarithromycin, in rare cases using spiramycin and Josamycin)
  • CNS: headache, dizziness, hearing loss (especially for erythromycin or clarithromycin)
  • Heart: prolongation of QT interval on the electrocardiogram
  • Local reactions: phlebitis and thrombophlebitis at the injection site

Drug interactions
Drug interactions of macrolides is based on the inhibition of cytochrome P-450 in the liver. The inhibition of cytochrome P-450 by macrolides can be classified as follows: clarithromycin> erythromycin> Josamycin = midekamitsin> roxithromycin> azithromycin> spiramycin. Macrolides inhibit metabolism and increase serum concentration of indirect anticoagulants, theophylline, carbamazepine, valproic acid, disopyramide, ergot drugs, cyclosporine. Do not combine macrolides (except spiramycin) with terfenadine, astemizole and cisapride because of the risk of serious cardiac arrhythmias caused by prolongation of QT interval.
Macrolides may increase the bioavailability of digoxin. Antacids reduce the absorption of macrolides, especially azithromycin, in the gastrointestinal tract. Rifampin enhances the metabolism of macrolides in the liver and reduces its concentration in the blood. Macrolides should not be combined with Lincosamides due to similar mechanism of action and possible agonism.