Macrolides

crop_square Key points

  • check_circle Bacteriostatic antibiotics with a macrocyclic lactone core
  • check_circle Inhibit bacterial protein biosynthesis by binding to the 50S ribosomal subunit
  • check_circle Broad spectrum of activity including obligate anaerobes and atypical bacteria
  • check_circle May cause gastrointestinal side effects due to prokinetic properties

crop_square Background and biochemistry

Macrolide antibiotics were isolated from Streptomyces bacteria. The term 'macrolide' is derived from the shared molecular structure of these antibiotics, a macrocyclic lactone ring. Macrolides may be produced entirely synthetically, but fermentation is still the preferred industrial method. Erythromycin was the first macrolide to be discovered and marketed. However, it quickly showed some disadvantages like low bioavailability. Subsequently developed macrolides, like clarithromycin and azithromycin, are erythromycin derivates.

crop_square Mechanism of action

Antibiotics of this group interfere with bacterial protein biosynthesis by binding to a specific receptor (23S ribosomal RNA) on the 50S subunit of the bacterial ribosome. Macrolides appear to globally inhibit protein biosynthesis by partially occluding the so-called 'exit-tunnel' of proteins that are being produced. They also seem to selectively inhibit the production of specific bacterial proteins crucial for cellular function. Macrolides are considered bacteriostatic but may be bactericidal at higher concentrations. Resistance against macrolides occurs due to modifications at the binding site and active drug efflux.

crop_square Drugs and spectrum of activity

  • Erythro­mycin
  • Clarithro­mycin
  • Azithro­mycin
All macrolides:

Clarithromycin and Azithromycin only:

All macrolides are active against a wide range of gram-positive bacteria and some gram-negatives. Clarithromycin and azithromycin show improved activity against some species, especially gram-negatives and anaerobes. Both drugs are used to eradicate Helicobacter pylori. Macrolides are frequently used in the treatment of respiratory tract infections to cover for atypical bacteria.

crop_square Pharmacokinetics

Macrolides are readily absorbed from the gastrointestinal tract, but bioavailability does not exceed 60%. When treating respiratory tract infections and pneumonia, there does not seem to be an advantage of intravenous administration over the oral route. Macrolides show good tissue penetrationbut do not cross the blood-brain barrier well. They are hepatically metabolised and mostly cleared via the faeces.

crop_square Adverse drug effects

Macrolides are known to cause gastrointestinal symptoms as they are motilin agonists. In fact, erythromycin is used as a prokinetic drug. They may cause cardiac arrhythmia by prolonging the QT interval. Some macrolides can be hepatotoxic.