Macrolide

See Also

Indications
Activity Spectrum

General Activity
1. Bacteria without cell walls (Mycoplasma, Legionella, Chlamydia)
2. Anaerobic Bacteria are partially covered by Extended Spectrum Macrolides (not Erythromycin)
3. Aerobic Bacteria
  1. Gram Positive Aerobes
  2. Gram Negative Aerobes (except Campylobacter, Pasteurella)
    1. Haemophilus Influenzae is covered by Extended Spectrum Macrolides, but not by Erythromycin
4. Macrolide resistance is increasing
  1. Resistance to one Macrolide is resistance to all Macrolides
Erythromycin
1. Major indications
  1. Chlamydia pneumoniae
  2. Chlamydia trachomatis
    1. Pneumoniae or Conjunctivitis
    2. Pelvic infection in pregnancy
  3. Legionella pneumophila
  4. Mycoplasma pneumoniae
  5. Bordetella pertussis
  6. Corynebacterium diphtheriae
  7. Campylobacter jejuni
2. Other organisms covered
Fidaxomicin (Dificid)
1. Indicated in Clostridioides difficile (Clostridium difficile)
2. Narrow spectrum Antibiotic (C. difficile, Staphylococcus, Enterococcus)
Extended Spectrum Agents
1. Coverage includes organisms covered by Erythromycin
2. Major Indications for extended spectrum agents
  1. Single dose Chlamydia trachomatis treatment
  2. Non-tuberculous Mycobacterial infections
  3. Helicobacter infections
  4. Respiratory infections
    1. Otitis Media (Azithromycin)
      1. Not recommended due to increased resistance rates
    2. Community Acquired Pneumonia
      1. Limit to suspected Mycoplasma pneumonia or Legionella pneumonia
      2. Macrolide resistant pneumococcus is common
      3. Consider Doxycycline as alternative
    3. Acute Sinusitis (Azithromycin)
      1. Not recommended due to growing resistance rates
    4. Streptococcal Pharyngitis
      1. Macrolides are only indicated in significant allergy to beta-lactams
3. Clarithromycin
  1. Streptococcus Pneumoniae (Pneumococcus)
  2. Staphylococcus aureus
  3. Toxoplasmosis gondii
  4. Mycobacterium leprae
  5. Mycobacterium Avium Complex
  6. Borrelia Burgdorferi
4. Azithromycin
  1. Haemophilus Influenzae
  2. Moraxella catarrhalis
  3. Toxoplasmosis gondii
  4. Mycobacterium Avium Complex (Clarithromycin better)
  5. Borrelia Burgdorferi

Precautions

Increasing Macrolide resistance for most indications (see below)
QT Prolongation with Azithromycin (see below)
Calcium Channel Blocker interaction with Clarithromycin (see below)
Macrolides in general (including Azithromycin) may increase heart defects with first trimester exposure of 5-7 days
1. Previously only Clarithromycin was considered a potential Teratogen (Cleft Lip association)
2. Fan (2020) BMJ 368: m331 +PMID:32075790 [PubMed]

Mechanism

Activity
1. Reversibly binds P Site on the 50s ribosomal subunit
2. Blocks translocation of polypeptide chain, therefore inhibiting Protein synthesis
Bacterial resistance mechanisms
1. Impermeability of Bacterial outer membranes (esp. Gram Negative Organisms)
2. Production of enzymes that alter ribosomal binding targets

Medications

Erythromycin Oral Preparations (Take with food to reduce GI Upset)
1. Erythromycin Base 1000 mg/day PO divided bid-qid
2. Erythromycin Ethyl Succinate (EES)
  1. Adult: 400 mg PO qid
  2. Child: 30-50 mg/kg/day PO divided qid
Erythromycin Parenteral Preparation: Erythromycin Lactobionate
1. Dose: 15 to 20 mg/kg/day IV divided every 6 hours
2. Maximum: 4 grams
Fidaxomicin (Dificid)
1. Indicated in Clostridioides difficile (Clostridium difficile)
2. Narrow spectrum Antibiotic (C. difficile, Staphylococcus, Enterococcus)
  1. Does not affect Gram Negative Bacteria including normal bowel flora
3. Minimal systemic absorption when taken orally
  1. As with oral Vancomycin, oral Fidaxomicin primarily stays in the Gastrointestinal Tract
Extended Spectrum Macrolides
1. Azithromycin
  1. Take more than 1 hour before or 2 hours after food
  2. Available in intravenous dosing
  3. Adult
    1. Day 1: 500 mg PO qd
    2. Day 2 to 5: 250 mg PO qd
  4. Child
    1. Day 1: 10 mg/kg PO qd (maximum: 500 mg)
    2. Day 2 to 5: 5 mg/kg PO qd (maximum: 250 mg)
  5. Infant under age 6 months
    1. 10 mg/kg/day for 5 days
2. Clarithromycin
  1. Dysgeusia or Distorted Taste (20%)
  2. May take with or without food
  3. Adult: 250 to 500 mg PO bid
  4. Child: 7.5 mg/kg PO bid
3. Telithromycin
  1. Discontinued in the United States
  2. Adult: 800 mg orally daily for 5 to 7 days
  3. Avoid in patients with Myasthenia Gravis due to risk of Respiratory Failure (FDA Black Box Warning)
  4. Similar to other Extended Spectrum Macrolides
    1. Appears to have greater activity for pneumococcus
    2. May be used in place of other broad spectrum agents
      1. Augmentin
      2. Extended spectrum Fluoroquinolones
  5. References
    1. Fogarty (2003) J Antimicrob Chemother 51:947-55 [PubMed]

Pharmacokinetics
Half Life

Clarithromycin: 5 hours
Telithromycin: 10 hours
Azithromycin: 68 hours

Adverse Effects

Nausea and Vomiting
1. Most with Erythromycin
2. Least with Azithromycin and Clarithromycin
QT Prolongation (see below)
1. Class effect with all Macrolides
2. Three fold increased risk of Sudden Cardiac Death while on Azithromycin
3. Ray (2013) N Engl J Med 366(20): 1881-90 [PubMed]

Drug Interactions

Interactions may also occur with extended spectrum
1. Clarithromycin
2. Telithromycin
3. Less likely to occur with Azithromycin
QT Prolongation (Erythromycin with an agent below)
1. Calcium Channel Blockers increase Erythromycin level
  1. Verapamil
  2. Diltiazem
2. Other potent CYP3A4 inhibitors
References
1. Ray (2004) N Engl J Med 351:1089-96 [PubMed]

References

(2013) Presc Lett 20(8): 44