Chapter 35  ·  Module 6  ·  Antibacterial Agents
Tetracyclines & Glycylcyclines
Mechanism, generations, adverse effects, and resistance at a glance
Abbreviations: tRNA = transfer RNA  ·  MDR = multidrug-resistant  ·  CRE = carbapenem-resistant Enterobacteriaceae  ·  MRSA = methicillin-resistant Staphylococcus aureus  ·  VRE = vancomycin-resistant Enterococcus  ·  RMSF = Rocky Mountain spotted fever  ·  FDA = US Food and Drug Administration  ·  CDC = Centers for Disease Control and Prevention
Tetracycline Generations — Key Comparisons
AgentOral BioavailabilityHalf-Life / DosingRenal FailureKey Gap
Tetracycline (1st gen) 60-80% fasting; food ↓ significantly 6-12 h; 4x/day Accumulates — contraindicated Multiple daily doses; food interactions
Doxycycline (2nd gen) ~93%; food acceptable 18-22 h; once-daily Safe — biliary/fecal elimination Photosensitivity; contraindicated in pregnancy/under age 8
Minocycline (2nd gen) ~95-100% ~16 h; twice-daily Safe — hepatic elimination Vestibular toxicity (reversible)
Tigecycline (glycylcycline) IV only — no oral formulation ~42 h IV; once-daily Safe (reduce in severe hepatic impairment) No Pseudomonas; low plasma levels — avoid for bacteremia
Key Clinical Indications
Doxycycline — Workhorse
Intracellular, Vector-Borne & More
  • RMSF, ehrlichiosis, anaplasmosis (drug of choice at any age)
  • Lyme disease (adults)
  • Chlamydia, Mycoplasma, Legionella
  • Brucella (+ rifampin), Q fever, anthrax
  • Community-acquired pneumonia (outpatient)
  • Malaria prophylaxis (chloroquine-resistant areas)
  • Acne and rosacea (anti-inflammatory doses)
Tigecycline — MDR Reserve Agent
Multidrug-Resistant Infections
  • CRE (non-bacteremic)
  • MRSA (non-bacteremic)
  • VRE
  • Extended-spectrum beta-lactamase producers
  • Polymicrobial infections including anaerobes
  • NOT for bacteremia (low plasma levels)
  • NOT for Pseudomonas aeruginosa
Resistance Mechanisms
MechanismHow It WorksTigecycline Overcomes?
Efflux pumps (tet A/B/C/E; tet K/L) Actively export tetracycline-Mg chelate complex from cell YES — bulky C-9 substituent prevents pump recognition
Ribosomal protection proteins (tet M/O/Q) GTPase proteins dislodge drug from 30S ribosomal binding site YES — 5x higher ribosomal affinity outcompetes protective proteins
Enzymatic inactivation (tet X variants) Flavoprotein hydroxylates tetracycline at C-11a position Emerging threat — tet X3/X4 variants can inactivate tigecycline
Key Rules

Doxycycline is safe in renal failure; tetracycline is not. Take oral tetracyclines 2 hours before or 4-6 hours after antacids, calcium, iron, and zinc. Contraindicated in pregnancy and children under 8 — except doxycycline for RMSF at any age (mortality risk outweighs dental risk).

Tigecycline has no Pseudomonas coverage and low plasma levels — do not use as monotherapy for bacteremia. FDA 2010: higher all-cause mortality with tigecycline vs. comparators across multiple indications.