Mechanism of Action
Erythromycin exerts its antimicrobial effect through a highly specific interaction with bacterial ribosomes. The drug binds reversibly to the 23S ribosomal RNA component of the 50S ribosomal subunit, specifically at the peptidyl transferase center near the A2058 and A2059 adenine residues (E. coli numbering). This binding site is located in domain V of the 23S rRNA, within the nascent peptide exit tunnel.
Molecular Interaction
The 14-membered lactone ring of erythromycin establishes multiple hydrogen bonds and hydrophobic interactions within the ribosomal binding pocket. The desosamine sugar at position C5 is critical for binding affinity, while the cladinose sugar at position C3 contributes to antibacterial potency. This binding blocks the translocation step of protein synthesis by preventing the movement of peptidyl-tRNA from the A-site to the P-site during elongation.
At therapeutic concentrations (0.5–2 μg/mL), erythromycin is primarily bacteriostatic. However, it exhibits bactericidal activity at higher concentrations (>4 μg/mL) or against highly susceptible organisms such as Streptococcus pyogenes and Streptococcus pneumoniae. The bacteriostatic nature allows host immune defenses to clear the infection while bacterial replication is halted.
Selective Toxicity
Erythromycin demonstrates selective toxicity for bacterial cells because mammalian ribosomes (80S) differ structurally from bacterial ribosomes (70S). The drug cannot bind effectively to the 60S subunit of eukaryotic ribosomes, ensuring minimal interference with human protein synthesis. However, erythromycin can affect mammalian mitochondrial ribosomes, which resemble bacterial ribosomes, potentially contributing to rare adverse effects like ototoxicity at high doses.
Bacterial Spectrum
Erythromycin exhibits broad-spectrum activity against gram-positive bacteria, select gram-negative organisms, and atypical pathogens. Its lipophilic nature allows penetration into phagocytes, enabling activity against intracellular pathogens.
Gram-Positive Coverage
Highly susceptible (MIC ≤0.5 μg/mL):
- Streptococcus pyogenes (Group A streptococci) — though resistance rates are increasing (10–40% in some regions)
- Streptococcus agalactiae (Group B streptococci)
- Streptococcus pneumoniae — penicillin-susceptible strains; resistance common in penicillin-resistant strains
- Corynebacterium diphtheriae — remains uniformly susceptible
- Listeria monocytogenes
- Erysipelothrix rhusiopathiae
Variably susceptible (MIC 0.5–4 μg/mL):
- Methicillin-susceptible Staphylococcus aureus (MSSA) — resistance emerging via efflux pumps
- Coagulase-negative staphylococci — often resistant in hospital settings
- Viridans group streptococci
- Enterococcus species — intrinsically less susceptible; not clinically reliable
Gram-Negative Coverage
Erythromycin has limited gram-negative activity due to poor penetration through the outer membrane. Susceptible organisms include:
- Haemophilus influenzae — MIC90 typically 4–8 μg/mL; azithromycin preferred
- Moraxella catarrhalis — generally susceptible
- Neisseria gonorrhoeae — resistance increasing globally
- Neisseria meningitidis — prophylaxis use only
- Bordetella pertussis — drug of choice for treatment and prophylaxis
- Campylobacter jejuni — resistance rates 0–30% depending on region
- Legionella pneumophila — excellent activity; penetrates alveolar macrophages
Most Enterobacteriaceae (E. coli, Klebsiella, Proteus) and Pseudomonas aeruginosa are intrinsically resistant due to impermeability and efflux mechanisms.
Atypical Pathogens
Erythromycin demonstrates excellent activity against cell wall-deficient and intracellular organisms:
- Mycoplasma pneumoniae — drug of choice; MIC typically <0.01 μg/mL
- Chlamydia trachomatis — effective for urogenital and ocular infections
- Chlamydophila pneumoniae — alternative to tetracyclines
- Ureaplasma urealyticum
- Treponema pallidum — alternative for penicillin-allergic patients (except neurosyphilis)
- Borrelia burgdorferi — early Lyme disease in penicillin-allergic patients
Resistance Mechanisms
Bacterial resistance to erythromycin has increased substantially since the 1990s, limiting its empiric use. Three primary mechanisms confer resistance:
Target Site Modification (erm genes)
The most common high-level resistance mechanism involves methylation of the 23S rRNA by erm-encoded methyltransferases. These enzymes add methyl groups to adenine residue A2058 in the peptidyl transferase center, preventing erythromycin binding. This modification confers cross-resistance to all macrolides, lincosamides (clindamycin), and streptogramin B antibiotics — termed MLSB resistance.
Expression patterns vary: constitutive expression (cMLSB) results in high-level resistance to all MLSB antibiotics, while inducible expression (iMLSB) may allow clindamycin susceptibility in vitro despite erythromycin resistance. The D-test identifies inducible resistance, important for preventing clindamycin treatment failure.
Active Efflux (mef and msr genes)
Efflux pumps actively export erythromycin from the bacterial cell, maintaining subinhibitory intracellular concentrations. The mef(A) gene encodes the predominant efflux pump in streptococci, conferring moderate resistance (MIC 1–32 μg/mL) to 14- and 15-membered macrolides but not 16-membered macrolides or clindamycin. This M-phenotype resistance is overcome at high drug concentrations.
The msr genes encode ABC transporters found primarily in staphylococci, providing resistance to macrolides and streptogramin B but not lincosamides.
Drug Inactivation
Enzymatic inactivation is less common but includes esterases (ere genes) that hydrolyze the macrolactone ring and phosphotransferases (mph genes) that modify hydroxyl groups. These enzymes are primarily found in Enterobacteriaceae and contribute to intrinsic resistance.
Clinical Impact
Resistance rates vary geographically and by pathogen:
- S. pneumoniae: 20–40% resistance in North America; >70% in some Asian countries
- S. pyogenes: 5–15% in the United States; >30% in some European and Asian regions
- MRSA: >90% resistant; MSSA: 15–50% resistant depending on local epidemiology
- M. pneumoniae: Emerging resistance in Asia (>90% in China); <10% in North America
Position Within Macrolide Class
Erythromycin is the prototypical first-generation macrolide antibiotic, characterized by a 14-membered lactone ring. Understanding its position relative to other macrolides helps clinicians select optimal therapy.
Structural Classification
14-membered macrolides:
- Erythromycin — the parent compound
- Clarithromycin — 6-O-methyl erythromycin; improved acid stability and oral bioavailability
- Roxithromycin — semi-synthetic derivative with longer half-life (not available in United States)
15-membered macrolides:
- Azithromycin — azalide subclass; nitrogen inserted into lactone ring; dramatically extended half-life (68 hours) and enhanced gram-negative activity
16-membered macrolides:
- Spiramycin — used primarily for toxoplasmosis in pregnancy
- Josamycin, midecamycin — not available in United States
Pharmacologic Advantages of Newer Macrolides
Second-generation macrolides (azithromycin, clarithromycin) were developed to address erythromycin's limitations:
Improved pharmacokinetics: Azithromycin's 68-hour half-life enables once-daily dosing and shorter treatment courses (3–5 days). Clarithromycin's 3–7 hour half-life allows twice-daily dosing versus erythromycin's 3–4 times daily requirement.
Better tolerability: Structural modifications reduce gastrointestinal side effects. Azithromycin and clarithromycin cause less motilin receptor stimulation, decreasing nausea, vomiting, and abdominal cramping compared to erythromycin.
Enhanced spectrum: Azithromycin provides superior coverage of Haemophilus influenzae (MIC90 0.5–2 μg/mL vs 4–8 μg/mL for erythromycin). Clarithromycin offers improved activity against atypical mycobacteria and Helicobacter pylori.
Reduced drug interactions: Azithromycin minimally inhibits CYP3A4, while erythromycin is a potent inhibitor. Clarithromycin has intermediate inhibition potential.
When Erythromycin Remains Preferred
Despite disadvantages, erythromycin maintains specific niches:
- Pregnancy: Category B rating (vs Category C for clarithromycin); preferred for chlamydial infections in pregnancy
- Neonatal prophylaxis: Ophthalmic ointment remains standard for preventing ophthalmia neonatorum
- Cost considerations: Generic erythromycin costs significantly less than branded azithromycin formulations
- Prokinetic effects: Utilized therapeutically for gastroparesis (though tachyphylaxis limits long-term use)
- Pertussis: Equivalent efficacy to azithromycin; either is acceptable for treatment/prophylaxis
Clinical Implications
Understanding erythromycin's mechanism, spectrum, and resistance patterns guides appropriate prescribing:
Empiric Therapy Considerations
High resistance rates limit erythromycin's role in empiric therapy for common infections. Local antibiograms should guide selection, but erythromycin is generally not recommended as empiric monotherapy for:
- Community-acquired pneumonia (except when covering atypicals in combination therapy)
- Skin and soft tissue infections in areas with high MRSA prevalence
- Streptococcal pharyngitis in regions with >10% resistance
Definitive Therapy
Erythromycin remains appropriate for culture-proven susceptible infections and specific clinical scenarios:
- Pertussis treatment and post-exposure prophylaxis
- Chlamydial infections in pregnancy
- Legionella pneumonia (with or without rifampin)
- Mycoplasma pneumoniae infections (monitor for resistance in Asia)
- Diphtheria (with antitoxin)
- Erythrasma
Combination Therapy
Erythromycin is sometimes combined with other antibiotics to broaden spectrum or prevent resistance:
- With penicillin for severe group A streptococcal infections (Eagle effect controversy)
- With rifampin for Legionella in severe cases
- Topical combination with benzoyl peroxide for acne (reduces resistance development)