Overview
Erythromycin (1952) and clarithromycin (1991) are both 14-membered ring macrolide antibiotics. Clarithromycin was developed as a semi-synthetic derivative of erythromycin with the goal of improving acid stability, oral bioavailability, and tolerability while maintaining antimicrobial efficacy.
The key structural difference is a single methyl group added at the 6-position of the erythromycin molecule (6-O-methylerythromycin), which produces substantial improvements in pharmacological properties.
Structural and Pharmacological Differences
Chemical Structure
- Erythromycin: 14-membered lactone ring with desosamine and cladinose sugars
- Clarithromycin: 6-O-methyl erythromycin (single methyl substitution at position 6)
Impact of 6-O-methylation:
- Increased acid stability → less degradation in stomach → higher bioavailability
- Enhanced tissue penetration
- Improved taste profile (though metallic taste remains)
- Active 14-hydroxyclarithromycin metabolite with antimicrobial activity
Pharmacokinetics Comparison
| Parameter | Erythromycin | Clarithromycin | Clinical Significance |
|---|---|---|---|
| Half-life | 1.5–2 hours | 3–7 hours (dose-dependent) | Clarithromycin allows twice-daily dosing |
| Bioavailability (oral) | 30–65% (variable, formulation-dependent) | 50–55% (consistent) | Clarithromycin more predictable absorption |
| Acid stability | Poor (requires enteric coating or ester) | Excellent (6× more stable than erythromycin) | Clarithromycin formulation simpler |
| Food effect | ↓ 25–50% (base/stearate); minimal (EES) | Minimal (may take with or without food) | Clarithromycin more flexible dosing |
| Active metabolite | None | Yes (14-OH-clarithromycin, antimicrobial) | Clarithromycin has dual activity (parent + metabolite) |
| Tissue penetration | Good (intracellular 10–40× serum) | Better (intracellular 20–60× serum) | Both excellent for intracellular pathogens |
| Protein binding | 70–80% | 65–75% | Similar |
| Metabolism | Hepatic (CYP3A4) | Hepatic (CYP3A4, autoinduction at high doses) | Both require caution in hepatic impairment |
| Excretion | Biliary (primary), renal (2–5%) | Renal (20–30%), biliary | Clarithromycin: dose adjust if CrCl <30 mL/min |
Clinical pearl: Clarithromycin's longer half-life and better acid stability translate to more convenient twice-daily dosing without food restrictions — a major practical advantage over erythromycin.
Bacterial Spectrum Comparison
Gram-Positive Coverage
| Organism | Erythromycin | Clarithromycin | Notes |
|---|---|---|---|
| Streptococcus pyogenes | Excellent (if susceptible) | Excellent (if susceptible) | Equivalent; cross-resistance common |
| Streptococcus pneumoniae | Good | Good | Equivalent; 20–40% resistance rates |
| MSSA | Good | Slightly better (2× lower MIC) | Clarithromycin modestly more potent |
| Listeria monocytogenes | Good | Good | Equivalent |
Gram-Negative Coverage
| Organism | Erythromycin | Clarithromycin | Winner |
|---|---|---|---|
| Haemophilus influenzae | Moderate (MIC90 4–8 μg/mL) | Better (MIC90 2–4 μg/mL); 14-OH metabolite excellent (MIC90 0.5–2 μg/mL) | Clarithromycin (metabolite is key) |
| Moraxella catarrhalis | Good | Excellent | Clarithromycin |
| Helicobacter pylori | Not used clinically | Excellent (MIC90 0.03–0.25 μg/mL) | Clarithromycin (unique indication) |
| Legionella pneumophila | Excellent | Excellent | Equivalent |
| Bordetella pertussis | Excellent | Excellent | Equivalent |
Atypical Pathogens
| Organism | Erythromycin | Clarithromycin |
|---|---|---|
| Mycoplasma pneumoniae | Excellent | Excellent |
| Chlamydia trachomatis | Good | Good |
| Chlamydophila pneumoniae | Good | Better (superior intracellular penetration) |
Mycobacteria (Clarithromycin's Unique Advantage)
- Mycobacterium avium complex (MAC):
- Erythromycin: No clinically useful activity
- Clarithromycin: Excellent activity (MIC90 2–8 μg/mL); first-line for MAC treatment and prophylaxis
- Mycobacterium leprae:
- Clarithromycin demonstrates activity in leprosy (investigational use)
Clinical implication: Clarithromycin's activity against H. pylori and MAC represents unique therapeutic niches not addressed by erythromycin.
Dosing and Convenience
Standard Dosing Regimens
| Indication | Erythromycin | Clarithromycin |
|---|---|---|
| Respiratory tract infections | 250–500 mg QID × 7–14 days (28–56 doses) |
250–500 mg BID × 7–14 days (14–28 doses) |
| Community-acquired pneumonia | 500 mg QID × 10–14 days (40–56 doses) |
500 mg BID × 7–14 days (14–28 doses) or XL 1000 mg daily × 7 days |
| Acute bacterial sinusitis | 500 mg QID × 10 days (40 doses) |
500 mg BID × 14 days or XL 1000 mg daily × 14 days |
| Skin infections | 250–500 mg QID × 7–10 days | 250 mg BID × 7–14 days |
| H. pylori eradication | Not used | 500 mg BID × 10–14 days (with PPI + amoxicillin or metronidazole) |
| MAC prophylaxis (HIV, CD4 <50) | Not used | 500 mg BID continuously |
| MAC treatment (disseminated) | Not used | 500 mg BID (with ethambutol ± rifabutin) |
Extended-release clarithromycin (Biaxin XL):
- 1000 mg once daily with food
- Approved for CAP, acute sinusitis
- Further improves adherence (once-daily dosing)
- Comparable efficacy to BID immediate-release
Tolerability Comparison
Gastrointestinal Side Effects
| Side Effect | Erythromycin | Clarithromycin |
|---|---|---|
| Nausea | 15–25% | 10–20% |
| Abdominal pain/cramping | 10–20% | 5–12% |
| Diarrhea | 10–15% | 6–10% |
| Vomiting | 5–10% | 3–6% |
| Any GI symptom | 20–30% | 10–20% |
| Discontinuation due to GI | 5–10% | 2–5% |
Mechanism: Both are motilin receptor agonists, but clarithromycin has weaker agonism → less GI motility stimulation → better tolerability.
Taste Disturbances
- Erythromycin: Bitter taste (10–15%), especially with liquid formulations
- Clarithromycin: Metallic/bitter taste (15–20%) — more common and distinctive than erythromycin
- Dysgeusia (altered taste) is a hallmark clarithromycin complaint
- "Everything tastes like metal" is pathognomonic for clarithromycin
- Resolves 1–2 weeks after discontinuation
Patient counseling: Warn patients starting clarithromycin about metallic taste (very common); reassure it is harmless and temporary.
Drug Interactions
CYP3A4 Inhibition Comparison
CYP3A4 Interaction Strength
- Erythromycin
- Strong inhibitor (80–90% enzyme inhibition)
- Clarithromycin
- Moderate inhibitor (40–60% enzyme inhibition)
- Clinical Impact
- Both cause significant interactions; erythromycin more potent
- Azithromycin (Reference)
- Minimal inhibitor (<10%) — preferred if interactions are concern
Key Drug Interactions (Both Agents)
| Drug Class | Erythromycin Effect | Clarithromycin Effect | Management |
|---|---|---|---|
| Statins (simva, lova, atorva) | ↑ 3–10× (high risk) | ↑ 2–5× (moderate risk) | Avoid simva/lova; reduce atorva 50%; use pravas/rosuva |
| Warfarin | ↑ INR significantly | ↑ INR moderately | Monitor INR closely; reduce warfarin 10–25% |
| Cyclosporine, tacrolimus | ↑ 2–5× (major) | ↑ 1.5–3× (moderate) | Reduce dose 50%; monitor levels closely |
| Theophylline | ↑ 50–75% | ↑ 20–40% | Monitor levels; reduce theophylline dose |
| Carbamazepine | ↑ 50–200% | ↑ 25–100% | Monitor levels; watch for toxicity |
| Ergot alkaloids | Contraindicated | Contraindicated | Do not combine (ergotism risk) |
| Colchicine | ↑ 3–8× (toxicity risk) | ↑ 2–5× (toxicity risk) | Reduce colchicine 50–75%; avoid if renal/hepatic impairment |
| Digoxin | ↑ 20–50% | ↑ 15–40% | Monitor levels; reduce digoxin dose |
Bottom line: Both agents have extensive drug interactions via CYP3A4 inhibition. Erythromycin is slightly more potent, but difference is clinically marginal. Azithromycin is strongly preferred when drug interactions are a concern.
For comprehensive interaction management, see the drug interactions page.
Cardiac Safety: QT Prolongation
| Parameter | Erythromycin | Clarithromycin |
|---|---|---|
| QTc prolongation | 5–30 ms (moderate) | 5–25 ms (moderate) |
| hERG channel blockade | IC50 ~20–80 μM | IC50 ~30–100 μM |
| Torsades de pointes risk | <0.1% | <0.1% |
| FDA warning | Yes (labeling) | Yes (labeling) |
| Clinical recommendation | Caution in at-risk patients | Caution in at-risk patients |
Verdict: Equivalent QT risk — both carry moderate prolongation potential. Azithromycin preferred if cardiac risk is primary concern.
For detailed cardiac risk assessment, see the QT prolongation page.
Pregnancy and Lactation
Pregnancy Safety
| Parameter | Erythromycin | Clarithromycin |
|---|---|---|
| FDA Category | B (safe) | C (use with caution) |
| Human data | Extensive (70+ years); no teratogenic effects | Limited; some studies suggest potential cardiovascular malformations |
| Animal data | No fetal harm | Fetal harm in rats, rabbits at high doses (cleft palate, cardiovascular anomalies) |
| Recommendation | Acceptable (avoid estolate) | Avoid if possible; use only if benefit clearly outweighs risk |
| Preferred alternative | N/A (erythromycin is the preferred macrolide) | Erythromycin or azithromycin |
Critical distinction: Clarithromycin is Category C due to animal teratogenicity data. While human data are reassuring (limited studies show no increased malformation risk), the FDA and most guidelines recommend avoiding clarithromycin in pregnancy when alternatives exist.
Clinical approach:
- If macrolide needed in pregnancy → choose erythromycin or azithromycin (both Category B)
- If patient already on clarithromycin and discovers pregnancy → discuss risks/benefits with OB; usually continue if >10 weeks gestation
- Never use clarithromycin as first-line in pregnancy
Lactation Safety
- Both compatible with breastfeeding (AAP, LactMed)
- Erythromycin: Relative infant dose 1–2%
- Clarithromycin: Relative infant dose 1–2%
- Monitor infant for diarrhea, oral thrush
Unique Clinical Indications
Clarithromycin-Specific Indications
Helicobacter pylori Eradication
Clarithromycin is a cornerstone of triple and quadruple therapy for H. pylori-associated peptic ulcer disease:
- Standard triple therapy (first-line):
- PPI (omeprazole, lansoprazole) BID
- Clarithromycin 500 mg BID
- Amoxicillin 1 g BID (or metronidazole 500 mg BID if penicillin-allergic)
- Duration: 14 days (preferred over 10 days)
- Eradication rate: 70–85% (declining due to clarithromycin resistance)
- Quadruple therapy (if clarithromycin resistance suspected):
- PPI BID + bismuth + tetracycline + metronidazole
- Clarithromycin resistance: 15–30% in U.S.; >50% in some countries; susceptibility testing recommended if available
Why erythromycin isn't used: Inferior H. pylori activity, poor GI tolerability (counterproductive in patients with peptic ulcers)
Mycobacterium Avium Complex (MAC)
Clarithromycin is first-line for MAC in HIV/AIDS patients and disseminated disease:
- MAC prophylaxis (HIV, CD4 <50 cells/μL):
- Clarithromycin 500 mg BID or azithromycin 1200 mg weekly
- Continue until CD4 >100 for ≥3 months on ART
- MAC treatment (disseminated or pulmonary):
- Clarithromycin 500 mg BID + ethambutol 15 mg/kg daily
- ± Rifabutin 300 mg daily (for severe disease)
- Duration: ≥12 months, often lifelong in immunocompromised
Why erythromycin isn't used: No meaningful activity against MAC
Erythromycin-Specific Indications
Gastroparesis (Prokinetic Effect)
- Indication: Diabetic gastroparesis, post-surgical gastric atony
- Mechanism: Motilin receptor agonism → increased gastric motility, accelerated emptying
- Dosing:
- IV: 250 mg over 30 min, 30 min before meals (acute setting)
- Oral: 250 mg TID before meals (chronic, though tachyphylaxis limits long-term use)
- Efficacy: 50–70% symptom improvement in acute use; less effective chronically
- Why clarithromycin isn't used: Weaker motilin agonism; erythromycin more effective as prokinetic
Neonatal Ophthalmic Prophylaxis
- Indication: Prevention of ophthalmia neonatorum (N. gonorrhoeae, C. trachomatis)
- Formulation: 0.5% erythromycin ophthalmic ointment
- Standard of care: Applied to both eyes within 1 hour of birth (universal prophylaxis in many countries)
- Why clarithromycin isn't used: No ophthalmic formulation available
Cost Comparison
Generic Pricing (U.S., 2024 estimates)
| Formulation | Erythromycin | Clarithromycin |
|---|---|---|
| Typical course cost (generic) | $10–20 (7-day, QID) | $20–40 (7-day, BID) |
| 14-day course (respiratory infection) | $15–30 | $30–60 |
| H. pylori 14-day course | N/A | $30–50 |
| Extended-release formulation | N/A | $40–80 (Biaxin XL) |
Cost-effectiveness: Erythromycin is cheaper per course, but clarithromycin may reduce indirect costs (better adherence, fewer side effects, unique indications with no alternatives).
Clinical Scenarios: When to Choose Each
Choose Clarithromycin When:
- H. pylori eradication — no erythromycin alternative (triple/quadruple therapy)
- MAC prophylaxis or treatment — first-line agent
- Community-acquired pneumonia — better H. influenzae coverage than erythromycin
- Twice-daily dosing preferred — improved adherence vs QID erythromycin
- Food-flexible dosing needed — can take with or without food
- Respiratory infections with likely H. influenzae — clarithromycin metabolite more active
- Non-pregnant patients — when pregnancy not a concern
Choose Erythromycin When:
- Pregnancy — Category B (clarithromycin is Category C, avoid)
- Gastroparesis — prokinetic effect needed (IV erythromycin)
- Cost-constrained setting — significantly cheaper
- Neonatal ophthalmic prophylaxis — standard 0.5% ointment
- Topical acne — established formulations (though clindamycin preferred)
- Patient metallic taste intolerance — if prior clarithromycin dysgeusia problematic
- Clarithromycin unavailable — formulary restrictions, supply issues
Either Macrolide Acceptable (Consider Other Factors):
- Streptococcal pharyngitis (penicillin-allergic patients) — azithromycin often preferred
- Legionella pneumonia — both effective; prefer azithromycin for convenience
- Mycoplasma pneumoniae — all macrolides effective
- Pertussis — azithromycin preferred (better tolerability, 5-day course)
- Skin/soft tissue infections — consider patient-specific factors
Resistance Patterns
Cross-Resistance
Resistance mechanisms affect both drugs identically:
- erm genes: Methylation of 23S rRNA → high-level resistance to both erythromycin and clarithromycin (and all macrolides)
- mef genes: Efflux pumps → moderate resistance to both 14-membered macrolides
- Clinical implication: If organism is erythromycin-resistant, it is also clarithromycin-resistant; switch to alternative class
H. pylori Clarithromycin Resistance
- Mechanism: A2143G and A2142G point mutations in 23S rRNA (not erm-mediated)
- Prevalence: 15–30% in U.S.; >50% in some Asian and European countries
- Impact: Eradication rates drop from 80–90% (susceptible) to <40% (resistant)
- Management:
- Obtain H. pylori culture and susceptibility when possible (endoscopic biopsy)
- If clarithromycin resistance documented or suspected (prior exposure, high-prevalence area), use bismuth-based quadruple therapy
- Avoid clarithromycin-containing regimens after prior failure
Summary Comparison Table
| Feature | Erythromycin | Clarithromycin | Advantage |
|---|---|---|---|
| Half-life | 1.5–2 h | 3–7 h | Clarithromycin |
| Dosing frequency | 2–4× daily | 2× daily (or 1× daily XL) | Clarithromycin |
| Acid stability | Poor (requires coating/ester) | Excellent | Clarithromycin |
| Food effect | Significant (base/stearate) | Minimal | Clarithromycin |
| Bioavailability | 30–65% (variable) | 50–55% (consistent) | Clarithromycin |
| GI side effects | 20–30% | 10–20% | Clarithromycin |
| Metallic taste | Uncommon | Common (15–20%) | Erythromycin |
| Drug interactions (CYP3A4) | Strong inhibitor | Moderate inhibitor | Clarithromycin (slightly weaker) |
| QT prolongation | Moderate | Moderate | Equivalent |
| H. influenzae activity | Moderate | Better (metabolite excellent) | Clarithromycin |
| H. pylori activity | Not used | Excellent (MIC <0.25) | Clarithromycin |
| MAC activity | None | Excellent (first-line) | Clarithromycin |
| Pregnancy category | B (safe) | C (avoid) | Erythromycin |
| Prokinetic effect | Strong (therapeutic use) | Weak | Erythromycin (for gastroparesis) |
| Cost (generic) | Lower ($10–20/course) | Higher ($20–40/course) | Erythromycin |
| Adherence | Lower (QID dosing) | Higher (BID dosing) | Clarithromycin |
The Bottom Line
Clarithromycin offers several advantages over erythromycin for most non-pregnant patients:
- Simpler dosing (BID vs QID) → better adherence
- Better tolerability (50% reduction in GI side effects)
- Food-flexible administration
- Superior H. influenzae coverage (active metabolite)
- Unique indications (H. pylori, MAC)
Erythromycin retains critical advantages in specific scenarios:
- Pregnancy — Category B vs Category C (non-negotiable preference)
- Gastroparesis — therapeutic prokinetic effect
- Cost — significantly cheaper in resource-limited settings
- Neonatal prophylaxis — established standard formulation
Key clinical decision point: Pregnancy status
- Pregnant or planning pregnancy: Erythromycin or azithromycin (both Category B) — never clarithromycin
- Not pregnant: Clarithromycin preferred for general infections (better adherence, tolerability); azithromycin preferred overall (fewest interactions, simplest dosing)
Clinical pearl: The 6-O-methyl modification that creates clarithromycin from erythromycin demonstrates elegant medicinal chemistry — a single structural change producing meaningful clinical improvements while creating unique therapeutic niches (H. pylori, MAC). However, the same modification unfortunately causes animal teratogenicity, limiting use in pregnancy and highlighting that no drug improvement comes without trade-offs.