Macrolides

Definition

Macrolides are a class of broad-spectrum bacteriostatic antibiotics characterized by a macrocyclic lactone ring, typically containing 14, 15, or 16 carbon atoms. They are primarily used to treat respiratory tract infections, skin and soft tissue infections, sexually transmitted diseases, and atypical infections, among others.

Macrolides are favored for their oral bioavailability, tissue penetration, and anti-inflammatory properties, and are often used in patients with penicillin allergy. Some agents have also demonstrated immunomodulatory effects independent of their antimicrobial action, particularly in chronic respiratory diseases.

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Mechanism of Action

Macrolides exert their antibacterial activity by binding to the 50S subunit of the bacterial ribosome, specifically at the 23S rRNA, inhibiting:

• Translocation of the growing peptide chain

• Protein elongation

• Peptidyl transferase activity

This results in inhibition of bacterial protein synthesis, leading to bacteriostatic effects. At higher concentrations or with highly susceptible organisms, some macrolides may exert bactericidal activity.

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Classification by Ring Size

Carbon Atoms in Lactone Ring	Examples	Features
14-membered	Erythromycin, Clarithromycin, Roxithromycin	Traditional macrolides; inhibit CYP3A4
15-membered (Azalides)	Azithromycin	Improved spectrum, tissue penetration, longer half-life
16-membered	Josamycin, Spiramycin, Midecamycin	Less CYP interaction, broader gram-positive coverage

Representative Macrolide Agents

Generic Name	Brand Name(s)	Route	Generation
Erythromycin	Erythrocin, Erythroped	Oral, IV	First-generation
Clarithromycin	Biaxin	Oral	Second-generation
Azithromycin	Zithromax, Z-Pak	Oral, IV	Azalide (15-membered)
Roxithromycin	Rulid	Oral	Second-generation
Spiramycin	Rovamycin	Oral	16-membered
Telithromycin	Ketek	Oral	Ketolide (related)
Fidaxomicin	Dificid	Oral (GI tract)	Macrocyclic (narrow spectrum)

Pharmacokinetics

Parameter	Erythromycin	Clarithromycin	Azithromycin
Absorption	Variable, acid labile	Well absorbed	Well absorbed
Bioavailability	~30–65%	~55%	~37%
Tissue penetration	Moderate	High	Very high
Half-life	1.5–2 hours	3–7 hours	~68 hours
Metabolism	Hepatic (CYP3A4)	Hepatic (CYP3A4)	Minimal
Excretion	Bile, urine	Urine, bile	Bile (mostly)

Azithromycin accumulates in macrophages, neutrophils, and epithelial cells, explaining its long duration of action and once-daily dosing.

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Spectrum of Activity

Macrolides are broad-spectrum agents, active against:

Gram-Positive Bacteria

• Streptococcus pyogenes

• Streptococcus pneumoniae (variable resistance)

• Staphylococcus aureus (MSSA only; not MRSA)

• Corynebacterium diphtheriae

• Listeria monocytogenes

Gram-Negative Bacteria

• Moraxella catarrhalis

• Haemophilus influenzae (especially with azithromycin, clarithromycin)

• Bordetella pertussis

• Neisseria gonorrhoeae (some strains)

Atypical Pathogens

• Mycoplasma pneumoniae

• Chlamydia trachomatis

• Chlamydia pneumoniae

• Legionella pneumophila

• Ureaplasma urealyticum

Other Pathogens

• Treponema pallidum (syphilis)

• Helicobacter pylori (clarithromycin component in triple therapy)

• Mycobacterium avium complex (MAC)

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Clinical Indications

1. Respiratory Tract Infections

   • Community-acquired pneumonia (CAP)

   • Pharyngitis, tonsillitis (esp. in penicillin-allergic patients)

   • Bronchitis (acute exacerbations of chronic bronchitis)

   • Pertussis (whooping cough)

2. Skin and Soft Tissue Infections

   • Impetigo, erysipelas, cellulitis (non-MRSA)

3. Sexually Transmitted Infections

   • Chlamydia urethritis/cervicitis

   • Gonorrhea (as part of combination therapy)

4. Helicobacter pylori Eradication

   • Clarithromycin-based triple therapy

5. Mycobacterial Infections

   • Azithromycin for MAC prophylaxis and treatment in HIV

   • Clarithromycin as a component of MAC therapy

6. Prophylaxis

   • Azithromycin for MAC in AIDS patients (CD4 <50)

   • Preoperative prophylaxis in dental and ENT surgery (in penicillin allergy)

7. Rheumatic Fever Prophylaxis

   • In patients with penicillin allergy (Erythromycin)

8. Ophthalmic Infections

   • Neonatal conjunctivitis (Chlamydia trachomatis)

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Resistance Mechanisms

Macrolide resistance is growing, especially among Streptococcus pneumoniae, S. pyogenes, and H. influenzae. Mechanisms include:

1. Target Site Modification

   • Methylation of 23S rRNA (erm gene) → prevents binding

   • Leads to MLSB resistance (Macrolide-Lincosamide-Streptogramin B)

2. Efflux Pumps

   • mef gene encodes macrolide efflux protein → lower intracellular concentration

3. Enzymatic Inactivation

   • Esterases or phosphotransferases degrade macrolides

4. Biofilm Formation

   • Reduces antibiotic penetration

Cross-resistance among 14- and 15-membered macrolides is common.

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Dosing Guidelines (Adults)

Drug	Common Dose	Duration
Erythromycin	250–500 mg QID or 500 mg BID	5–10 days
Clarithromycin	250–500 mg BID	7–14 days
Azithromycin	500 mg on Day 1, then 250 mg/day x 4	5-day "Z-Pak"
Azithromycin (Chlamydia)	1 g orally once	Single-dose therapy

Dose adjustment may be required in renal or hepatic impairment (varies by agent).

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Adverse Effects

System	Adverse Reactions
Gastrointestinal	Nausea, vomiting, abdominal pain, diarrhea (erythromycin most common)
Hepatic	Elevated transaminases, cholestatic hepatitis (rare)
Cardiac	QT prolongation, torsades de pointes (especially with clarithromycin, erythromycin)
CNS	Headache, dizziness, tinnitus (less common)
Allergic	Rash, pruritus, anaphylaxis (rare)
Others	Taste disturbances (clarithromycin), injection site reactions (IV forms)

Contraindications

• Hypersensitivity to macrolide class

• Concomitant use with drugs that prolong QT interval (e.g., amiodarone, sotalol)

• Severe hepatic impairment (particularly for erythromycin estolate)

• Use with ergot alkaloids (risk of ergotism)

• Myasthenia gravis: may exacerbate symptoms

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Drug Interactions

Macrolides, especially erythromycin and clarithromycin, are potent CYP3A4 inhibitors, leading to drug accumulation of co-administered substrates.

Interacting Drug	Risk
Warfarin	↑ INR, bleeding
Statins (simvastatin, lovastatin)	↑ Myopathy, rhabdomyolysis risk
Theophylline	↑ Theophylline toxicity
Digoxin	↑ Plasma levels, toxicity
Benzodiazepines	Enhanced sedation (midazolam, triazolam)
QT-prolonging drugs	Additive effect → arrhythmias

Azithromycin has minimal CYP3A4 inhibition, making it preferred in polypharmacy.

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Use in Special Populations

Pediatrics

• Widely used; azithromycin is preferred for respiratory infections and otitis media

• Dosing based on weight (e.g., 10 mg/kg on Day 1, then 5 mg/kg)

Pregnancy

• Erythromycin and azithromycin are Category B

• Clarithromycin is Category C – use only if necessary

Geriatrics

• Increased risk of cardiac adverse effects, especially QT prolongation

• Renal and hepatic function should guide clarithromycin use

Hepatic Impairment

• Erythromycin: Use with caution or avoid

• Clarithromycin: Use cautiously, monitor LFTs

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Comparative Insights

Agent	Half-life	Tissue Penetration	QT Risk	CYP3A4 Inhibition
Erythromycin	Short	Moderate	High	High
Clarithromycin	Moderate	High	Moderate	Moderate
Azithromycin	Long (~68 h)	Very high	Low–moderate	Minimal

Regulatory Approvals

• All major macrolides are FDA- and EMA-approved for a wide range of infections

• Fidaxomicin is approved for Clostridioides difficile infection (CDI) and is not absorbed systemically

• Some agents (e.g., telithromycin) have restricted use due to hepatotoxicity and vision changes

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Current Research Directions

1. Macrolides as Immunomodulators

   • Chronic inflammatory diseases (e.g., diffuse panbronchiolitis, cystic fibrosis)

2. Antiviral Applications

   • Investigated in viral pneumonia, including COVID-19 (azithromycin)

3. Anti-biofilm Activity

   • Prevent biofilm formation in Pseudomonas and Staphylococcus

4. Macrolide Resistance Genes Surveillance

   • mef, erm, msr genes under global epidemiological monitoring

5. Novel Derivatives and Formulations

• Labeled azithromycin for targeted delivery, nanoparticle formulations