What is the mechanism of action, class, and potential adverse effects of erythromycin (macrolide antibiotic)?

Erythromycin: Mechanism of Action, Class, and Adverse Effects

Erythromycin is a macrolide antibiotic that inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit, causing various adverse effects including gastrointestinal disturbances, QT prolongation, and potential drug interactions through CYP3A inhibition.

Mechanism of Action

Erythromycin exerts its antimicrobial activity through a specific mechanism:

• Binds to the 50S subunit of the bacterial ribosome, specifically at the polypeptide exit region 1
• Inhibits RNA-dependent protein synthesis by blocking the translocation reaction during protein synthesis 2
• Acts as a modulator of translation rather than a global inhibitor of protein synthesis, selectively inhibiting the translation of a subset of cellular proteins 3
• Generally bacteriostatic, but can be bactericidal against autolytic species such as pneumococci 1

Antibiotic Class

Erythromycin belongs to the macrolide class of antibiotics:

• Macrolides are characterized by a large lactone ring structure
• The class includes erythromycin, clarithromycin, and azithromycin (an azalide, which is closely related) 1
• Exhibits better antibacterial activity in neutral to basic pH environments 1
• Has reduced activity in acidic conditions due to becoming positively charged, which limits membrane penetration 1

Antimicrobial Spectrum

Erythromycin demonstrates activity against:

• Gram-positive bacteria: Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Corynebacterium species, Listeria monocytogenes 4
• Gram-negative bacteria: Bordetella pertussis, Haemophilus influenzae, Legionella pneumophila, Neisseria gonorrhoeae 4
• Atypical pathogens: Mycoplasma pneumoniae, Chlamydia trachomatis, Treponema pallidum, Ureaplasma urealyticum 4
• Limited activity against Enterobacteriaceae and Pseudomonas aeruginosa 2

Pharmacokinetics

Key pharmacokinetic properties include:

• Oral absorption of erythromycin base and its salts in microbiologically active form 4
• Significant inter-individual variations in absorption 4
• Largely protein-bound in plasma 4
• Readily diffuses into most body fluids 4
• Concentrated in the liver and excreted in bile with normal hepatic function 4
• Less than 5% of the administered dose recovered in active form in urine 4
• Optimal blood levels achieved when taken in the fasting state (at least 30 minutes and preferably 2 hours before meals) 4

Adverse Effects

Gastrointestinal Effects

• Most frequent side effects are gastrointestinal and dose-related 4
• Include nausea, vomiting, abdominal pain, diarrhea, and anorexia 4, 1
• Epigastric distress and abdominal cramps are common 1

Cardiovascular Effects

• Associated with QT prolongation and ventricular arrhythmias 4
• Can cause ventricular tachycardia and torsades de pointes 4

Hepatic Effects

• May cause symptoms of hepatitis, hepatic dysfunction, and abnormal liver function tests 4
• Cholestatic hepatitis has been reported 1

Hypersensitivity Reactions

• Range from urticaria to anaphylaxis 4
• Skin reactions from mild eruptions to erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis (rare) 4

Other Adverse Effects

• Infantile hypertrophic pyloric stenosis (IHPS) in neonates during the month after administration 1
• Interstitial nephritis 4
• Rare reports of pancreatitis and convulsions 4
• Reversible hearing loss, particularly in patients with renal insufficiency or receiving high doses 4
• Pseudomembranous colitis 4
• Sensorineural hearing loss 1

Drug Interactions

Erythromycin has significant potential for drug interactions:

• Inhibits the cytochrome P450 enzyme system (CYP3A subclass) 1
• Coadministration with drugs metabolized by CYP3A can increase their concentrations and effects 1
• Contraindicated with astemizole, cisapride, pimazole, or terfenadine due to risk of serious cardiovascular adverse events 1
• Interacts with numerous medications including:
  • Alfentanil, bromocriptine, cyclosporine, carbamazepine
  • Disopyramide, dihydroergotamine, ergotamine
  • Lovastatin, simvastatin, methylprednisolone
  • Quinidine, rifabutin, tacrolimus
  • Triazolo-benzodiazepines and related benzodiazepines
  • Sildenafil, zidovudine, phenytoin, valproate
  • Theophylline, digoxin, oral anticoagulants 1
• Antagonism exists in vitro between erythromycin and clindamycin, lincomycin, and chloramphenicol 4

Resistance Mechanisms

Bacterial resistance to erythromycin occurs through several mechanisms:

• Major route is modification of the 23S rRNA in the 50S ribosomal subunit 4
• Efflux mechanisms can also be significant 4
• Resistance can be encoded by erm(B) gene (high-level resistance) or mef(A) gene (lower-level resistance) 1
• Increasing prevalence of macrolide resistance to S. pneumoniae globally, ranging from <10% to >90% 1
• Extensive macrolide use provides strong selective pressure for resistance development 1

Clinical Applications

Erythromycin is used for various infections, though increasing resistance has limited its utility in some settings:

• Respiratory tract infections, particularly when atypical pathogens are suspected 1
• Skin and soft tissue infections caused by susceptible organisms 4
• Treatment and post-exposure prophylaxis for pertussis 1
• Alternative for patients with penicillin allergy 5

Special Considerations

• Pregnancy Category B drug - animal studies show no risk to fetus, but adequate human studies are lacking 1
• Not recommended for severe streptococcal infections due to bacteriostatic nature and increasing resistance 5
• Should be used with caution in neonates due to risk of IHPS 1
• Newer macrolides (azithromycin, clarithromycin) often preferred due to better tolerability and pharmacokinetic profiles 6