One class, one ribosomal target, three very different drugs at the bedside. What separates them is half-life, CYP3A4 inhibition, and which indications still hold up against current guidelines.
| Azithromycin15-membered azalide | Clarithromycin14-membered | Erythromycin14-membered, the original | |
|---|---|---|---|
| Half-life | ~68 h | 3–7 h | 1.5–2 h |
| Typical adult dose | 500 mg day 1, then 250 mg days 2–5; or 500 mg daily × 3 | 500 mg twice daily | 250–500 mg every 6 h |
| Renal adjustment | None | Halve dose if CrCl < 30 | None |
| CYP3A4 inhibition | Minimal | Strong | Moderate |
| Atypicals | Excellent | Excellent | Good |
| S. pneumoniae | Resistance is shared across the class; above 25% in most US regions | ||
| H. influenzae | Good | Moderate (helped by 14-OH metabolite) | Poor |
| H. pylori | No | Only with confirmed susceptibility | No |
| MAC | Yes | Yes | No |
| Anaerobes | Poor | Poor | Poor |
| QT prolongation | All three; highest with IV erythromycin; FDA warning for azithromycin | ||
| Distinct use | Pertussis (incl. infants < 1 mo), typhoid, traveler's diarrhea, trachoma, COPD exacerbation prevention | MAC treatment | Prokinetic: gastroparesis, pre-endoscopy in upper GI bleed |
Bold marks the agent that stands out on that row. Red marks an interaction risk worth checking before you prescribe.
A widely shared comparison chart gets the pharmacokinetics mostly right and the indications out of date.
What the chart has right: the half-lives, the CYP3A4 ranking, MAC coverage, and erythromycin's prokinetic role.
The workhorse. Atypical coverage for inpatient CAP alongside a β-lactam, pertussis, enteric infections, and long-term COPD exacerbation prevention. Few drug interactions, once-daily dosing, and a tissue half-life that makes short courses work.
A backbone of MAC treatment, and H. pylori therapy when susceptibility is known. Otherwise the interaction burden usually makes azithromycin the better choice.
Now mostly a motilin agonist. A single IV dose 30–120 minutes before endoscopy in upper GI bleeding clears the stomach and improves the view. Also used for gastroparesis, with tachyphylaxis over weeks.
Clarithromycin and erythromycin raise CYP3A4 substrate levels. Simvastatin and lovastatin are contraindicated (rhabdomyolysis). Colchicine can reach fatal levels, especially with renal or hepatic impairment. Expect higher apixaban and rivaroxaban exposure.
Calcium channel blockers. In older adults, clarithromycin with a CCB was associated with more hypotension and acute kidney injury than azithromycin with the same CCB.
QT risk adds up. Check the baseline QTc, potassium, and magnesium before stacking a macrolide with ondansetron, haloperidol, a fluoroquinolone, or methadone. IV erythromycin carries the highest arrhythmia risk of the three.
Infants. Erythromycin in the first weeks of life is linked to hypertrophic pyloric stenosis. Azithromycin is the preferred agent for pertussis under 1 month of age.
All three bind the 50S ribosomal subunit and block protein synthesis. They are bacteriostatic at usual doses and concentrate inside cells, which is why they cover intracellular organisms like Legionella, Chlamydia, and Mycoplasma. GI upset is the most common adverse effect. It is a direct motilin effect, and strongest with erythromycin.