What are macrolides?

Antibacterial macrolides are widely prescribed drugs for an even wider variety of infections. Here, we review the macrolides pharmacology you need to know.

We discuss the indications that macrolides are licensed to treat, how they work, what side effects they’re linked to, and what drug interactions you need to bear in mind.

Examples of antibacterial macrolides include:

• Erythromycin
• Clarithromycin
• Fidaxomicin
• Azithromycin

Like aminoglycosides, macrolides work as protein synthesis inhibitors. The first widely used macrolide, erythromycin, has a relatively broad spectrum of activity. Later macrolides have greater activity against Gram-negative organisms.

Indications

Macrolides are used in the treatment of a wide range of infections – both Gram-positive and Gram-negative infections.

These indications include:

• Respiratory infections
• Skin and soft tissue infections
• Severe pneumonia
• Eradication of Helicobacter pylori infection

In the case of H. pylori infection, macrolides are used alongside other drugs – typically a penicillin and a proton-pump inhibitor (what is referred to as “triple therapy”).

Patients who are allergic to penicillins can be given metronidazole instead.

Fidaxomicin is a narrow-spectrum drug that selectively inhibits Clostridium difficile infections.

Mechanism of Action

As we have alluded to, antibacterial macrolides are protein synthesis inhibitors.

More specifically, macrolides bind to the 50S ribosomal subunit; binding that results in blockade of the translocation process which is needed for the polypeptide chain to grow and elongate.

This process is bacteriostatic. Fidaxomicin is different, in that its actions are bactericidal, and it works by binding to the switch regions of RNA polymerase.

Earlier macrolides had broader spectrum of activity. Erythromycin, for example, has relatively broad activity against both Gram-positive and Gram-negative organisms. Later macrolides, such as clarithromycin and azithromycin, have more activity against Gram-negative organisms.

However, bacterial resistance to macrolides is relatively common, often caused by mutations within the ribosome that prevent the macrolide from binding.

Side Effects and Clinical Factors

Side effects are more pronounced with earlier macrolides, like erythromycin. This is particularly true for gastrointestinal side effects such as nausea, vomiting, abdominal pain, and diarrhea (erythromycin has a gastroprokinetic effect).

When administered via the intravenous route, thrombophlebitis (inflammation of a vein due to thrombus formation).

Other side effects of macrolides include:

• Allergies
• Antibiotic-linked colitis
• Cholestatic jaundice
• QT prolongation

At high doses, macrolides can cause ototoxicity.

QT prolongation is more likely if macrolides are administered alongside other drugs that also prolong the QT interval – such as SSRIs, antipsychotics, quinine, and fluoroquinolones.

Given that macrolides interact with many CYP enzymes, there are important drug interactions to consider. Taking macrolides with statins can, for example, increase the risk of myopathies. Both erythromycin and clarithromycin inhibit CYP enzymes, whereas azithromycin does not. Similarly, taking macrolides with warfarin can increase the risk of bleeding.

As macrolides are metabolized via hepatic routes, patients with liver disease may experience more pronounced side effects. Caution is therefore warranted. Dose reduction is warranted in patients with severe renal impairment

That’s about it for our rapid summary of macrolides pharmacology. Return to our NAPLEX blog soon for more great content on macrolides and every other antibacterial drug class you are expected to know.