Macrolide antibiotics have a similar spectrum of action to penicillins and include azithromycin, clarithromycin, and erythromycin. They are often used in penicillin allergic patients to treat infections such as pneumonia and cellulitis. Erythromycin can also be used for its prokinetic properties (unlicensed in the UK), due to its action at motilin and serotonin 5HT3 receptors. Marcolides exert their antibacterial action by selectively binding to the 50s ribosomal subunit of susceptible bacteria, which prevents translocation of activated amino acids, inhibiting bacterial protein synthesis. The following article will describe their spectrum of activity, pharmacokinetic properties, cautions and contraindications for use and interactions. adobe stock Fig 1: Mechanisms of action of antimicrobials Spectrum of Activity Both clarithromycin and erythromycin are active against gram-positive, gram-negative bacteria and Mycoplasma. Clarithromycin is also active against anaerobes. Azithromycin is less active against Gram-positive bacteria compared to erythromycin, but more effective against certain Gram-negative organisms such as Haemophilus influenzae. Azithromycin is commonly used in urethral and sexually transmitted infections, and for its anti-inflammatory effects in bronchiectasis (three times weekly). Cautions and Adverse Effects Common adverse effects of macrolides usually affect the gastrointestinal tract and include nausea, diarrhoea and vomiting. However like with other broad spectrum antibiotics, there is a risk of pseudomembranous colitis (including Clostridium difficile) with macrolide therapy, commonly associated with hospital stays, therefore in severe diarrhoea stool samples should be taken to rule this out. All macrolides are primarily excreted via the liver, therefore caution should be taken in hepatic impairment, and hepatic dysfunction has been reported with erythromycin. Furthermore there is a MHRA alert in relation to cardiotoxicity with erythromycin use. Caution should be taken in the following conditions: coronary artery disease, severe cardiac insufficiency, conduction disturbances or clinically relevant bradycardia and patients susceptible to QT prolongation. Other adverse effects include: Can exacerbate weakness in myasthenia gravis. QT prolongation risk → increased with age, electrolyte disturbances (hypokalaemia, hypomagnesaemia), or other QT-prolonging drugs. Rare but serious allergic reactions (e.g., Stevens-Johnson syndrome). A 2-3 increase in the risk of infantile hypertrophic pyloric stenosis with erythromycin (rare) azithromycin and clarithromycin Contraindications Both erythromycin and clarithromycin are contraindicated in patients with a history of QT prolongation, ventricular arrhythmia and electrolyte disturbances (hypokalaemia, hypomagnesaemia). Clarithromycin is also contraindicated in severe hepatic impairment when alongside renal impairment. Azithromycin is contraindicated in severe renal impairment (eGFR <10 mL/min) and should be used with caution in liver disease. Drug Interactions All macrolides Contraindicated with ergot derivatives (e.g. dihydroergotamine and ergotamine)→ risk of vasospasm and ischaemia. Avoid with other QT-prolonging drugs (risk of arrhythmia). All inhibit P-glycoprotein (P-gp) → ↑ P-gp substrate levels (e.g. digoxin, colchicine) Colchicine toxicity risk (substrate for both CYP3A4 & P-gp). Erythromycin & Clarithromycin Both erythromycin and clarithromycin are potent CYP3A4 inhibitors and CYP3A4 substrates themselves, leading to many interactions. Clarithromycin demonstrates stronger CYP3A4 inhibition, therefore exhibits more severe interactions. Rivaroxaban, apixaban, warfarin: increased risk of bleeding Both are contraindicated with: simvastatin (↑ risk of rhabdomyolysis), furthermore with astemizole, cisapride, domperidone, pimozide, and terfenadine due to the risk of QT prolongation. Clarithromycin is contraindicated with midazolam (↑7-fold exposure), lovastatin (↑ risk of rhabdomyolysis), lomitapide (risk ↑ transaminases), ticagrelor, ivabradine and ranolazine. Cautioned with oral hypoglycaemic agents and/or insulin (risk of hypoglycaemia). Sub-therapeutic levels of erythromycin and clarithromycin when administered with CYP3A4 inhibitors (e.g., rifampicin, phenytoin, carbamazepine, St John’s wort) Azithromycin Minimal CYP3A4 inhibition → fewer interactions. Still inhibits P-gp. Interactions: ciclosporin (↑ levels, monitor), antacids (↓ Cmax → separate by 1h before/2h after). CYP3A4 inhibitors CYP3A4 inducers Potent Moderate CiclosporinErythromycin Clarithromycin Ketoconazole Voriconazole Itraconazole Posaconazole HIV Protease inhibitors Diltiazem Verapamil Fluconazole Amiodarone RifampicinSt John’s Wort Table 1: CYP3A4 inducers and inhibitors Pharmacokinetic Properties Formulations Erythromycin and clarithromycin are also available as intravenous formulations. Erythromycin is also available in different forms. Erythromycin base is unstable in gastric acid therefore this is only deliverable orally via a gastrointestinal resistant tablet. Erythromycin stearate and erythromycin ethylsuccinate are less susceptible to degradation by gastric acid so are deliverable orally without gastric protection. Erythromycin stearate is a salt formulation which dissociates and subsequently is absorbed in the intestine Erythromycin ethylsuccinate is an ester formulation that is principally absorbed in the small intestine and when it reaches the plasma, esterases release the active drug The following table describes the pharmacokinetic properties of oral macrolide antibiotics. Pharmacokinetic parameter Erythromycin (PO) Clarithromycin (PO) Azithromycin (PO) Absorption Cmax ~1 h. Acid-labile → given as base (enteric coated), stearate (salt), or ethylsuccinate (ester) Rapid, well absorbed. Food delays Tmax but not bioavailability. Css ~ 2 days F = 37%. Tmax = 2–3 h. Distribution Widely distributed into tissues 80% bound to plasma proteins Extensive tissue binding. Variable protein binding depending on concentration Metabolism CYP3A4 metabolism (limited overall) CYP3A4 metabolism → active metabolite. Inhibits CYP3A4 (inhibits its own metabolism) Minimal metabolism. ~10 metabolites (not clinically active) Excretion Mainly biliary (≈95%). ~5% renal. Faeces & urine. 18% parent compound in urine, 4% in faeces Mainly biliary. Small renal contribution. t½ 2–4 days (long). No evidence of change to PK in hepatic insufficiency – may be renal compensation Half-life (t½) ~2 h ~5–7 h (parent drug), longer with metabolite 2–4 days Key PK Features Short half-life → frequent dosing. Acid unstable → different salt/ester forms used Inhibits CYP3A4 strongly. Active metabolite adds antimicrobial activity Long half-life → once-daily dosing. Minimal CYP interactions References https://bnf.nice.org.uk/treatment-summaries/macrolides/ accessed 27.1.25 https://www.medicines.org.uk/emc/product/7072/smpc#gref accessed 28.1.25 P.G. Davey, The pharmacokinetics of clarithromycin and its 14-OH metabolite, Journal of Hospital Infection, Volume 19, Supplement A, 1991, Pages 29-37, ISSN 0195-6701, https://doi.org/10.1016/0195-6701(91)90215-T. https://www.medicines.org.uk/emc/product/502/smpc#gref accessed https://www.medicines.org.uk/emc/product/404/smpc accessed 4.2.25 https://bnf.nice.org.uk/drugs/erythromycin/ accessed 4.2.25 Jennifer L. Davis, Chapter 2 – Pharmacologic Principles, Editor(s): Stephen M. Reed, Warwick M. Bayly, Debra C. Sellon, Equine Internal Medicine (Fourth Edition), W.B. Saunders, 2018, Pages 79-137, ISBN 9780323443296, https://doi.org/10.1016/B978-0-323-44329-6.00002-4.(https://www.sciencedirect.com/science/article/pii/B9780323443296000024) https://bnf.nice.org.uk/drugs/azithromycin/ accessed 4.2.25 https://www.medicines.org.uk/emc/product/2272/smpc accessed 4.2.25 https://bnf.nice.org.uk/drugs/clarithromycin/#indications-and-dose accessed 4.2.25 https://www.uptodate.com/contents/image?imageKey=EM/73326 accessed 5.2.25 Do you think you’re ready? Take the quiz below Pro Feature - Quiz Macrolides Question 1 of 3 Submitting... Skip Next Rate question: You scored 0% Skipped: 0/3 More Questions Available Upgrade to TeachMePharmacy Pro Challenge yourself with over 200 multiple-choice questions to reinforce learning. Learn More Rate This Article