Macrolide antibiotics are, to put it at its simplest, antibiotics which contain a macrocyclic lactone ring. These drugs work by interfering with bacterial protein synthesis, and their action is primarily bacteriostatic in effect. This means that macrolides are not structured to positively kill bacteria, but what they do is stem bacterial growth. Examples of macrolide antibiotics include erythromycin, azithromycin and clarithromycin – some of which may be used as replacements in penicillin-allergic patients. First, though, let’s take a closer look at the pharmacology of macrolide antibiotics – how and why they work.
Pharmacology of Macrolide Antibiotics
Macrolides are drugs which contain a macrocyclic lactone ring (see here for more information on the medicinal chemistry of macrolides). A macrocycle is simply a macromolecule in cyclic form – usually containing between 8 and 12 atoms. In this case, the macrocyclic lactone is often linked to various deoxy sugars – such as cladinose. Macrolide antibiotics are – depending on which drug is deployed – used in the treatment of gram-positive infections and a limited number of gram-negative infections. Streptococci, enterococci, pneumococci and staphylococci are typically sensitive to the action of macrolides.
Mechanism of Action
Macrolide antibiotics interfere with protein synthesis as their mechanistic mode. Specifically, these drugs bind – reversibly – to the P site on the 50S portion of the bacterial ribosome. As a result of this binding, tRNA is dissociated from its translocation site, thereby perilously damaging the protein synthesis sequence. It’s worth re-emphasising that this interference with protein synthesis is not bactericidal but is, instead, bacteriostatic in effect. In summary, bacteriostatic macrolides bind reversibly to the P site of the 50S ribosome, displacing tRNA and disrupting translation.
Resistance & Pharmacokinetics
The pharmacology of macrolide resistance is not well studied. Resistance to macrolide antibiotics is common, and may manifest in different ways. The most common mechanism of resistance is methylation of the 23S portion of the bacterial ribosome – a process which can occur either through chromosomal or plasmid-mediated means. Other mechanisms – though less frequent – include the use of efflux pumps.
Erythromycin is destroyed at acid pH and must therefore be given as an enteric-coated tablet (or, alternatively, as an ester prodrug). It may also be delivered intravenously. Clarithromycin, unlike its erythro-cousin, is acid-stable. However, clarithromycin undergoes hefty first-pass metabolism in the liver. Both of these drugs have short half-lives – usually between 1 and 3 hours.
Azithromycin, unlike erythromycin, is poorly absorbed from the gut. The drug is widely distributed and released quite slowly into each tissue. Azithromycin is excreted into the bile unchanged and has – in contrast to the macrolides described above – a long half-life of approximately 1-2 days (depending on dosing). The final macrolide – telithromycin – is well absorbed from the gut and has a half-life of approx. 10 hours.
Nausea, vomiting, diarrhoea and epigastric discomfort are quite common with oral erythromycin. This is in contrast with azithromycin and clarithromycin which are considerably better tolerated. It has been reported that myopathy may occur if statins are taken together with certain macrolides, and their combination is therefore not advised. Clarithromycin and erythromycin both inhibit CYP3A4, but not azithromycin. QT prolongation may also occur, as with cholestatic jaundice with erythromycin.
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