Macrolide Antibiotics Used in Pediatric Age

Select a topic Classification Mechanism of Action Indications Pharmacokinetics Dosing Adverse Effects Contraindications Drug Interactions Antibiotic Resistance Select a drug Erythromycin Azithromycin Clarithromycin

Classification of Macrolide Antibiotics

Macrolide antibiotics are a class of drugs characterized by a large macrocyclic lactone ring. They are broadly classified into three generations:

1. First Generation:
   • Erythromycin
2. Second Generation:
   • Clarithromycin
   • Azithromycin
3. Third Generation:
   • Ketolides (e.g., Telithromycin) - not approved for pediatric use

In pediatric practice, the most commonly used macrolides are erythromycin, azithromycin, and clarithromycin.

Mechanism of Action

Macrolides exert their antimicrobial effect through the following mechanisms:

1. Protein Synthesis Inhibition: They bind reversibly to the 50S subunit of bacterial ribosomes, specifically to the 23S rRNA molecule. This inhibits peptidyl transferase activity, preventing peptide bond formation and subsequent protein synthesis.
2. Translocation Inhibition: Macrolides interfere with the translocation of tRNA from the A-site to the P-site on the ribosome, further disrupting protein synthesis.
3. Anti-inflammatory Effects: In addition to their antimicrobial properties, macrolides have been shown to have immunomodulatory and anti-inflammatory effects, which can be beneficial in certain respiratory conditions.

The antimicrobial spectrum of macrolides includes:

• Gram-positive bacteria (e.g., Streptococcus pneumoniae, Streptococcus pyogenes)
• Some gram-negative bacteria (e.g., Haemophilus influenzae, Moraxella catarrhalis)
• Atypical pathogens (e.g., Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila)

Indications in Pediatrics

Macrolides are used in various pediatric infections, including:

1. Respiratory Tract Infections:
   • Community-acquired pneumonia (particularly atypical pneumonia)
   • Acute otitis media (as an alternative in penicillin-allergic patients)
   • Streptococcal pharyngitis (in penicillin-allergic patients)
   • Pertussis (treatment and prophylaxis)
2. Skin and Soft Tissue Infections:
   • Impetigo
   • Cellulitis (in penicillin-allergic patients)
3. Sexually Transmitted Infections:
   • Chlamydia trachomatis infections in adolescents
4. Mycobacterial Infections:
   • Prophylaxis and treatment of Mycobacterium avium complex (MAC) in HIV-infected children
5. Other Indications:
   • Gastroparesis (erythromycin as a prokinetic agent)
   • Chronic inflammatory lung diseases (e.g., cystic fibrosis, bronchiectasis) - for their anti-inflammatory properties

Pharmacokinetics in Pediatrics

Understanding the pharmacokinetics of macrolides is crucial for their appropriate use in children:

1. Absorption:
   • Erythromycin: Variably absorbed, acid-labile
   • Clarithromycin: Well-absorbed, not affected by food
   • Azithromycin: Well-absorbed, decreased by food
2. Distribution:
   • All macrolides distribute widely throughout the body
   • Achieve high intracellular concentrations
   • Penetrate well into respiratory tissues and fluids
3. Metabolism:
   • Erythromycin and Clarithromycin: Extensively metabolized by CYP3A4
   • Azithromycin: Minimal hepatic metabolism
4. Elimination:
   • Erythromycin: Primarily biliary excretion
   • Clarithromycin: Both renal and biliary excretion
   • Azithromycin: Primarily biliary excretion
5. Half-life:
   • Erythromycin: 1.5-2 hours
   • Clarithromycin: 3-4 hours
   • Azithromycin: 68 hours (tissue half-life)

The long tissue half-life of azithromycin allows for once-daily dosing and shorter treatment courses in many indications.

Dosing in Pediatrics

Dosing of macrolides in children varies based on the specific drug, indication, and patient factors:

1. Erythromycin:
   • 30-50 mg/kg/day divided every 6-8 hours (max 2 g/day)
   • For pertussis: 40-50 mg/kg/day divided every 6 hours for 14 days
2. Clarithromycin:
   • 15 mg/kg/day divided every 12 hours (max 1 g/day)
   • For MAC prophylaxis in HIV: 7.5 mg/kg (max 500 mg) twice daily
3. Azithromycin:
   • Acute otitis media: 30 mg/kg as a single dose or 10 mg/kg once daily for 3 days
   • Community-acquired pneumonia: 10 mg/kg (max 500 mg) on day 1, followed by 5 mg/kg (max 250 mg) once daily for 4 days
   • Pertussis: 10 mg/kg (max 500 mg) on day 1, then 5 mg/kg (max 250 mg) once daily for 4 days

Note: Dosing may need adjustment in renal impairment, particularly for clarithromycin.

Adverse Effects

While generally well-tolerated, macrolides can cause various adverse effects:

1. Gastrointestinal:
   • Nausea, vomiting, abdominal pain, diarrhea (most common)
   • Erythromycin is associated with more GI side effects than newer macrolides
2. Hepatotoxicity:
   • Rare but can occur, particularly with erythromycin estolate
   • Monitor liver function tests in prolonged therapy
3. Cardiac:
   • QT interval prolongation (risk varies among macrolides)
   • Torsades de pointes (rare but serious)
4. Ototoxicity:
   • Reversible hearing loss (rare, usually with high doses or prolonged use)
5. Allergic Reactions:
   • Rash, urticaria, anaphylaxis (rare)

Azithromycin generally has the most favorable side effect profile among macrolides.

Contraindications and Precautions

Macrolides should be used with caution or avoided in certain situations:

1. Hypersensitivity: Known allergy to any macrolide antibiotic
2. Hepatic Impairment: Use with caution, monitor liver function
3. Myasthenia Gravis: May exacerbate symptoms
4. Long QT Syndrome: Increased risk of arrhythmias
5. Pregnancy: Erythromycin preferred if a macrolide is necessary
6. Concurrent Use of QT-prolonging Medications: Increased risk of arrhythmias

Always consider the risk-benefit ratio, especially in patients with pre-existing conditions or those on multiple medications.

Drug Interactions

Macrolides, especially erythromycin and clarithromycin, have numerous drug interactions due to their inhibition of CYP3A4:

1. CYP3A4 Substrates:
   • Increased levels of: statins, benzodiazepines, cyclosporine, tacrolimus
   • Potential for increased toxicity
2. QT-prolonging Drugs:
   • Antiarrhythmics, antipsychotics, antihistamines
   • Increased risk of arrhythmias
3. Anticoagulants:
   • May increase INR with warfarin
4. P-glycoprotein Substrates:
   • May increase levels of digoxin

Azithromycin has fewer drug interactions compared to erythromycin and clarithromycin, making it a preferred choice in patients on multiple medications.

Antibiotic Resistance

Macrolide resistance is an increasing concern in pediatric practice:

1. Mechanisms of Resistance:
   • Target site modification (e.g., methylation of 23S rRNA)
   • Efflux pumps
   • Enzymatic inactivation (rare)
2. Prevalence:
   • Varies geographically and by pathogen
   • High rates in some Streptococcus pneumoniae and Streptococcus pyogenes strains
3. Cross-resistance:
   • Resistance to one macrolide often confers resistance to others
4. Prevention Strategies:
   • Judicious use of macrolides
   • Adherence to local antibiotic guidelines
   • Consideration of local resistance patterns

Monitoring local resistance patterns is crucial for effective empiric therapy with macrolides in pediatric infections.

Erythromycin

Erythromycin is a first-generation macrolide antibiotic, discovered in 1952.

Key Characteristics:

• Available in various salt forms (e.g., estolate, ethylsuccinate, stearate)
• Relatively short half-life (1.5-2 hours)
• More prone to gastrointestinal side effects than newer macrolides

Pediatric Uses:

1. Treatment of pertussis (whooping cough)
2. Alternative for penicillin-allergic patients in streptococcal pharyngitis
3. Treatment of atypical pneumonia
4. Prophylaxis for rheumatic fever
5. Prokinetic agent in gastroparesis

Dosing in Children:

• General dosing: 30-50 mg/kg/day divided every 6-8 hours (max 2 g/day)
• Pertussis treatment: 40-50 mg/kg/day divided every 6 hours for 14 days

Advantages:

• Long history of use and well-understood safety profile
• Inexpensive compared to newer macrolides
• Effective against many atypical pathogens

Disadvantages:

• Higher incidence of gastrointestinal side effects
• More frequent dosing required due to short half-life
• More drug interactions due to strong CYP3A4 inhibition
• Increasing resistance among some pathogens

Azithromycin

Azithromycin is a second-generation macrolide antibiotic, introduced in the 1980s.

Key Characteristics:

• Long half-life (68 hours) allows for once-daily dosing and short treatment courses
• Better tissue penetration compared to erythromycin
• Fewer drug interactions due to minimal CYP3A4 inhibition

Pediatric Uses:

1. Community-acquired pneumonia
2. Acute otitis media
3. Treatment and prophylaxis of pertussis
4. Streptococcal pharyngitis in penicillin-allergic patients
5. Mycoplasma genitalium infections in adolescents
6. Traveler's diarrhea

Dosing in Children:

• Acute otitis media: 30 mg/kg as a single dose or 10 mg/kg once daily for 3 days
• Community-acquired pneumonia: 10 mg/kg (max 500 mg) on day 1, followed by 5 mg/kg (max 250 mg) once daily for 4 days
• Pertussis: 10 mg/kg (max 500 mg) on day 1, then 5 mg/kg (max 250 mg) once daily for 4 days

Advantages:

• Convenient once-daily dosing
• Short treatment courses (often 3-5 days)
• Better gastrointestinal tolerability than erythromycin
• Fewer drug interactions

Disadvantages:

• Higher cost compared to erythromycin
• Concerns about potential for inducing antimicrobial resistance due to long half-life
• Some concerns about cardiovascular safety, though risk appears low in children

Clarithromycin

Clarithromycin is a second-generation macrolide antibiotic, introduced in the 1990s.

Key Characteristics:

• Better acid stability than erythromycin
• Forms an active metabolite (14-hydroxyclarithromycin) with additional antimicrobial activity
• Intermediate half-life (3-4 hours) allows for twice-daily dosing

Pediatric Uses:

1. Community-acquired pneumonia
2. Acute otitis media
3. Pharyngitis/tonsillitis in penicillin-allergic patients
4. Skin and soft tissue infections
5. Mycobacterium avium complex (MAC) prophylaxis in HIV-infected children
6. H. pylori eradication (as part of combination therapy)

Dosing in Children:

• General dosing: 15 mg/kg/day divided every 12 hours (max 1 g/day)
• MAC prophylaxis in HIV: 7.5 mg/kg (max 500 mg) twice daily

Advantages:

• Better gastrointestinal tolerability than erythromycin
• Twice-daily dosing improves compliance compared to erythromycin
• Active metabolite enhances effectiveness against certain pathogens (e.g., H. influenzae)
• Good tissue penetration, especially in respiratory tract

Disadvantages:

• More drug interactions than azithromycin due to CYP3A4 inhibition
• Higher cost than erythromycin
• Taste disturbances more common than with other macrolides
• Not approved for children under 6 months of age