Macrolides

Macrolides (erythromycin, clarithromycin, azithromycin) are bacteriostatic protein synthesis inhibitors with activity against Gram-positive cocci and atypical and intracellular bacteria: Mycoplasma, Chlamydia, Legionella, Bordetella and Campylobacter. They also have immunomodulatory and prokinetic effects used outside infection. They carry important cardiac and drug interaction risks.

Mechanism. Binding to the 23S rRNA of the 50S ribosomal subunit blocks peptide chain elongation (translocation). Activity is largely time-dependent for erythromycin and clarithromycin and AUC to MIC dependent for azithromycin.

Pharmacokinetics. Erythromycin absorption is variable and acid-labile (enteric-coated or ester forms), half-life about 2 hours. Clarithromycin is better absorbed with a half-life of 3 to 7 hours and an active hydroxy metabolite. Azithromycin has extensive tissue and intracellular accumulation with a half-life of about 68 hours, allowing short courses. Biliary excretion is the main route.

Resistance. Ribosomal methylation (erm genes) causing cross-resistance with lincosamides and streptogramin B, efflux (mef genes), and 23S rRNA mutations in Mycoplasma pneumoniae and Mycoplasma genitalium. Macrolide resistance in pneumococci, Group A streptococci and Staphylococcus aureus is common in many areas.

• Erythromycin: cheapest; frequent dosing; gastrointestinal intolerance; strong CYP3A4 inhibitor; prokinetic via motilin receptor.
• Clarithromycin: the most active against H. pylori and non-tuberculous mycobacteria; strongest CYP3A4 and P-glycoprotein inhibition.
• Azithromycin: best activity against Haemophilus, Moraxella and Gram-negative enterics such as Salmonella and Shigella (resistance increasing), fewest interactions, once-daily short courses.

Adult regimens (normal renal function).

• Community pneumonia (atypical cover): azithromycin 500 mg daily for 3 days (or 500 mg then 250 mg daily for 4 days), or clarithromycin 500 mg every 12 hours for 5 to 7 days. Legionella: azithromycin 500 mg daily for 7 to 10 days, or a fluoroquinolone.
• Pertussis: azithromycin 500 mg on day 1 then 250 mg daily for 4 days.
• Genital chlamydia: doxycycline is preferred; azithromycin 1 g orally once is an alternative, including in pregnancy.
• Cholera: azithromycin 1 g orally once. Enteric fever (uncomplicated): azithromycin 1 g on day 1 then 500 mg daily for 6 days.
• Helicobacter pylori: clarithromycin 500 mg every 12 hours within combination regimens where local resistance is under 15 percent.
• Erythromycin 250 to 500 mg orally every 6 hours (up to 4 g daily); IV 500 mg to 1 g every 6 hours. Prokinetic use: 125 to 250 mg orally before meals, or 250 mg IV 30 to 120 minutes before endoscopy in upper gastrointestinal bleeding.
• Prophylaxis: azithromycin 1200 mg weekly for Mycobacterium avium complex in advanced HIV when needed; 250 mg daily or 500 mg three times weekly to reduce exacerbations in selected patients with COPD, bronchiectasis or cystic fibrosis after exclusion of non-tuberculous mycobacteria and QT prolongation.
• Mass treatment: azithromycin 20 mg/kg once (maximum 1 g) for trachoma, and 30 mg/kg once (maximum 2 g) for yaws.
• Children: azithromycin 10 mg/kg once daily for 3 days (maximum 500 mg); erythromycin 30 to 50 mg/kg daily in divided doses; clarithromycin 15 mg/kg daily in two divided doses.

Selection. Atypical cover in pneumonia, penicillin allergy as an alternative for streptococcal infection, pertussis, chlamydia, Campylobacter, cholera, and immunomodulatory use. Not reliable alone for pneumococcal or Group A streptococcal infection where resistance is high.

Contraindications. Hypersensitivity; history of QT prolongation or torsades; concurrent drugs that prolong QT or inhibit CYP3A4 where interaction is dangerous (clarithromycin and erythromycin with simvastatin, lovastatin, ergot alkaloids, colchicine in renal or hepatic impairment); prior macrolide-related cholestatic hepatitis.

Serious effects. QT prolongation and torsades (erythromycin highest, then clarithromycin, then azithromycin) and increased cardiovascular death with azithromycin in high-risk patients; cholestatic hepatitis (erythromycin estolate); infantile hypertrophic pyloric stenosis in infants under 6 weeks; reversible hearing loss with high-dose IV therapy; worsening of myasthenia gravis; C. difficile infection; gastrointestinal upset.

Interactions.

• Erythromycin and clarithromycin inhibit CYP3A4: simvastatin, lovastatin (contraindicated), atorvastatin, colchicine, calcineurin inhibitors, carbamazepine, warfarin, rivaroxaban, apixaban, sildenafil, midazolam, ergotamine, theophylline, digoxin.
• Combination with other QT-prolonging drugs (fluoroquinolones, antipsychotics, ondansetron, methadone) raises risk.
• Azithromycin has few CYP effects.

Monitoring. ECG baseline for patients with cardiac disease, electrolyte disturbance or interacting drugs; potassium and magnesium; liver tests for courses over 2 weeks; hearing with prolonged high doses.

Special groups.

• Pregnancy: erythromycin (base or stearate, not estolate) and azithromycin are acceptable; clarithromycin is avoided in the first trimester unless needed.
• Breastfeeding: compatible, with monitoring of the infant for diarrhoea, rash and pyloric stenosis in the first weeks.
• Renal impairment: azithromycin needs no adjustment; clarithromycin is halved when creatinine clearance is under 30 mL/min; erythromycin maximum about 1.5 g daily in severe impairment.
• Hepatic impairment: avoid erythromycin estolate; use caution with others.
• Older adults: higher risk of QT effects and interactions.
• Region: azithromycin mass treatment is used for trachoma in several East African countries, and macrolide resistance in pneumococci and typhoidal Salmonella needs surveillance.