Tetracyclines are a class of broad-spectrum antibiotics indicated for a wide variety of bacterial infections. These medications bind the 30S ribosomal subunit to inhibit protein synthesis of bacteria. Tetracyclines cover gram-positive and gram-negative organisms, as well as atypical bacteria such as chlamydia, mycoplasma, spirochetes, and even protozoa. The oral absorption of tetracyclines is decreased with the ingestion of some medications and supplements (e.g., milk of magnesia) or food (e.g., dairy products) that contain polyvalent cations, such as calcium and magnesium. Adverse effects include photosensitivity, GI upset, and skin pigmentation in the case of minocycline. Tetracyclines suppress bone growth and discolor teeth in children and are contraindicated in pregnancy and breastfeeding. Of importance, 3 new tetracyclines were approved by the FDA in 2018, which may have a role in treating certain infections due to drug-resistant organisms.

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Chemistry and Pharmacodynamics

Chemical structure

  • Contain a linear, fused 4-ring nucleus
  • Have a variety of attached functional groups
Chemical structure of tetracyclines

Chemical structure of tetracycline

Image: “Skeletal formula of tetracycline” by Vaccinationist. License: Public Domain

Mechanism of action

  • Tetracyclines bind reversibly to the 30S ribosomal subunit:
    • Block the attachment of aminoacyl-tRNA to the mRNA–ribosome complex
    • Disrupt bacterial protein synthesis
  • Bacteriostatic (inhibit but do not kill organisms)
  • Demeclocycline is an antidiuretic hormone (ADH) antagonist at the renal tubule as well.
Tetracycline site of action on 30S ribosomal subunit

Tetracycline site of action on 30S ribosomal subunit

Image by Lecturio. License: CC BY-NC-SA 4.0


  • Absorption: 
    • Oral dosage forms well absorbed
    • Absorption is decreased within 1–2 hours after consumption of dairy products, antacids, and any other products containing iron, magnesium, calcium, or aluminum (e.g., supplements, vitamins), as these elements can bind with tetracyclines and reduce their ability to be absorbed.
  • Distribution: 
    • Adequately distributed in body fluid 
    • Poor CSF penetration except for minocycline
    • Minocycline is most lipophilic → achieves therapeutic CSF levels 
    • Minocycline distribution ↑ in saliva and tears
    • Doxycycline distribution ↑ in prostatic fluids 
  • Metabolism: The majority of 1st-generation tetracyclines are not metabolized.
  • Excretion:
    • Primarily renal excretion
    • Doxycycline excreted via bile/feces


Table: Tetracyclines and their indications
(oral tablet)
  • Actinomycosis: when penicillin contraindicated
  • Gram-negative infections:
    • Klebsiella
    • Escherichia coli
    • Acinetobacter
    • Bacteroides
    • Enterobacter
    • Shigella
  • Acne: Cutibacterium (Propionibacterium) acnes
  • Respiratory infections:
    • Haemophilus influenzae
    • Streptococcus pneumoniae
    • S. pyogenes
    • Klebsiella
    • Mycoplasma pneumoniae
  • Skin and soft tissue infections (SSTIs)
    • Staphylococcus aureus
    • S. pyogenes
  • Urinary tract infections (UTIs)
    • Klebsiella
    • E. coli
  • STDs
    • Chlamydia trachomatis
    • Lymphogranuloma venereum
    • Chancroid (Haemophilus ducreyi)
    • Syphilis (Treponema pallidum)—when penicillin contraindicated
  • Ophthalmic infections: Chlamydia trachomatis (conjunctivitis)
  • Yaws: Treponema pertenue
  • Amebiasis: Entamoeba histolytica
  • Anthrax
    • Bacillus anthracis
    • When penicillin contraindicated
  • Vincent infection (acute necrotizing ulcerative gingivitis)
    • Fusobacterium fusiforme
    • When penicillin contraindicated
  • Listeriosis
    • Listeria monocytogenes
    • When penicillin contraindicated
  • Cholera: Vibrio cholerae
  • Relapsing fever: Borrelia recurrentis
  • Rickettsial infections
    • Typhus group
    • Rocky Mountain spotted fever
    • Coxiella burnetii (Q fever)
  • Zoonotic infections:
    • Bartonella
    • Brucellosis (Mediterranean/undulant fever): in conjunction with aminoglycoside
    • Tularemia: Francisella tularensis
    • Plague: Yersinia pestis
    • Psittacosis (parrot fever): Chlamydia psittaci
Off-label use: part of multidrug treatment for Helicobacter pylori (peptic ulcer disease)
  • Oral tablet
  • Oral capsule
  • Oral syrup/suspension
  • Injection solution (IV)
Tetracycline indications, plus:
  • Lyme disease (Borrelia spp.)
  • Rosacea (inflammatory lesions only)
  • Community-acquired pneumonia
  • Staphylococcus aureus skin infections, including MRSA
  • Prophylaxis of Plasmodium falciparum (malaria)
  • 1st-line treatment for Lyme disease unless contraindicated
  • Doxycycline activity > tetracycline
  • No dose adjustment in renal dysfunction
  • Oral tablet
  • Oral capsule
  • Injection solution (IV)
Tetracycline indications, plus:
  • Meningococcal carrier state
  • Meningitis: Neisseria meningitidis
  • Atypical mycobacteria
  • Numerous bacterial targets and indications
  • Rarely used now as an antibacterial agent
  • Used in the treatment of chronic SIADH
  • Induces nephrogenic diabetes insipidus
(injection solution (IV))
  • Community-acquired pneumonia
  • SSTIs, including MRSA
  • Vancomycin-resistant enterococcus (VRE)
  • Intraabdominal infections, including MRSA
  • Derivative of tetracyclines, actually a glycylcycline
  • Use when no alternatives and/or tetracycline resistance present
  • IV use only
  • No dose adjustment in renal dysfunction
  • Not for use in bloodstream infections
  • Not susceptible to tetracycline-resistance mechanisms

Adverse Effects and Contraindications

Adverse effects

  • GI upset: 
    • Nausea and vomiting most common side effects
    • Advise patients to consume medication with water and sit upright for 30 minutes after ingestion to prevent esophagitis.
  • Photosensitivity of the skin:
    • Chemical interaction between drug/metabolite in the skin and UV rays may cause a severe sunburn-like reaction.
    • Advise patients to avoid direct sunlight and artificial UV rays (i.e., tanning beds) and wear protective clothing and sunscreen.
  • ↓ Bone growth: children < 8 years old
  • Tooth yellowing and enamel hypoplasia: typically in children < 8 years old
  • Hepatotoxicity
  • Vestibular dysfunction with minocycline or doxycycline
  • Drug-induced lupus-like reaction with minocycline
  • Fanconi syndrome with expired tetracyclines


  • Pregnancy (category D):
    • May cause congenital defects, hepatotoxicity in the mother, and abnormal tooth development as above
    • The exception is doxycycline for treatment of Rickettsia spp.
  • Children < 8 years old except for doxycycline for treatment of Rickettsia spp.
  • Renal failure except with doxycycline because of its GI elimination


  • Breastfeeding:
    • Present in breast milk in small amounts
    • Avoid prolonged or repeated courses.
    • Short-term use acceptable
    • Previous theoretical concern for staining of infants; teeth and possible bone deposition inhibiting growth, but recent research suggests these are unlikely
  • Preexisting liver disease/failure: High doses may lead to liver toxicity. 
  • Drug–drug interactions:
    • Anticonvulsants: decrease tetracycline effectiveness and alter anticonvulsant drug levels
    • Warfarin: ↑ INR
    • Oral contraceptives: decreased effectiveness
  • Black box warning for tigecycline: associated with ↑ mortality

Mechanisms of Resistance

  • Development of plasma-mediated efflux pumps for active ejection, limiting ability of the drug to accumulate in cells
  • Decreased cell-wall penetration
  • Ribosomal protection proteins prevent binding.
  • Enzymatic destruction

Comparison of Medications

Table: Comparison of Tetracyclines
MedicationPharmacokineticsIndicationAdverse effects
  • Absorbed orally
  • Excreted via kidneys and bile
  • Respiratory infections
  • SSTIs
  • Acne
  • Clostridial infections
  • STIs
  • Anthrax
  • Zoonotic infections
  • GI upset
  • Tooth staining
  • Esophagitis
  • Absorbed orally
  • Excreted via bile/feces
  • Like tetracycline, plus:
    • Spirochete infections
    • Community-acquired pneumonia
  • More effective for acne
  • GI upset
  • Most photosensitizing
  • Esophagitis
  • Absorbed orally
  • Excreted via kidneys and bile
Like tetracycline, plus:
  • Neisseria meningitidis
  • Atypical mycobacteria
  • GI upset
  • Least photosensitizing
  • Tooth staining
  • Slate-gray pigmentation of skin
  • Lupus-like reaction


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