Tetracyclines and Glycylcyclines
Tetracyclines inhibit 30S ribosomal binding of aminoacyl-tRNA and have broad spectrum activity including intracellular pathogens and zoonotic infections.
## Overview
Tetracyclines are broad-spectrum bacteriostatic antibiotics that inhibit bacterial protein synthesis. They have re-emerged as important drugs due to doxycycline's versatility against intracellular pathogens, rickettsial diseases, and as an oral option for community-acquired infections. Tigecycline, a glycylcycline, overcomes key tetracycline resistance mechanisms.
## Mechanism of Action
Tetracyclines enter bacteria by passive diffusion and energy-dependent transport. They chelate Mg²⁺ and bind the 30S ribosomal subunit (16S rRNA, A-site), preventing attachment of aminoacyl-tRNA to the acceptor site, thereby halting peptide chain elongation. Bacteriostatic against most organisms.
## Individual Agents
**Tetracycline**: First-generation; limited use now due to resistance and chelation issues. Must be taken on an empty stomach; calcium, iron, and antacids chelate and prevent absorption.
**Doxycycline**: Most widely used tetracycline. Less affected by dietary calcium than tetracycline. Hepatic elimination (renally safe in renal impairment). Used for: CAP (atypicals), Lyme disease (all stages in adults), Rocky Mountain spotted fever (drug of choice, including in children despite tooth staining risk in severe cases), chlamydia, gonorrhea (alternative), PID, malaria prophylaxis, brucellosis, tularemia, anthrax (post-exposure prophylaxis), acne.
**Minocycline**: High lipophilicity; CNS penetration; used for MRSA skin infections (though inferior to TMP-SMX), Acinetobacter (minocycline-susceptible strains). Vestibular side effects (dizziness, ataxia).
**Tigecycline** (glycylcycline): Modified tetracycline backbone that evades both tetracycline efflux pumps and ribosomal protection proteins. Covers MRSA, VRE, ESBL-producers, carbapenem-resistant Acinetobacter, and anaerobes. High tissue distribution (low serum levels — NOT for bacteremia). Clinical trials showed increased mortality vs. comparators in VAP and bacteremia — use with caution.
## Resistance
Two main mechanisms: 1) Efflux pumps (Tet proteins — energy-dependent export of drug from cell) — does NOT affect tigecycline. 2) Ribosomal protection proteins (TetM, TetO — GTP-dependent displacement of tetracycline from ribosome) — also does NOT affect tigecycline due to steric modifications.
## Adverse Effects
- **Tooth discoloration and bone growth inhibition**: Chelation with calcium in developing teeth/bones; contraindicated in children <8 years and pregnancy (except Rocky Mountain spotted fever — benefits outweigh risks)
- **Photosensitivity**: Especially doxycycline; advise sun protection
- **GI irritation**: Take with food (except tetracycline); esophageal ulceration if taken without water while supine
- **Hepatotoxicity**: High-dose IV tetracycline (largely historical); mild elevation with standard doses
- **Intracranial hypertension**: Pseudotumor cerebri (rare)
## Key Takeaways
- Tetracyclines block aminoacyl-tRNA binding to the 30S ribosomal A-site; bacteriostatic
- Doxycycline is the drug of choice for rickettsial diseases, Lyme disease, and atypical pneumonia
- Tigecycline overcomes efflux pump and ribosomal protection resistance but is associated with increased mortality in VAP/bacteremia
- Contraindicated in children <8 years and pregnancy due to tooth/bone effects