Tetracyclines

Definition and Therapeutic Role
Tetracyclines are a class of broad-spectrum bacteriostatic antibiotics that inhibit bacterial protein synthesis by binding to the 30S ribosomal subunit, thereby preventing the attachment of aminoacyl-tRNA to the mRNA-ribosome complex. They are active against a wide variety of Gram-positive and Gram-negative bacteria, intracellular pathogens, rickettsiae, chlamydiae, mycoplasmas, and certain protozoa. In addition to infectious diseases, they have anti-inflammatory and immunomodulatory properties, which make them useful in non-infectious conditions such as acne and rosacea.

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Mechanism of Action

Tetracyclines bind reversibly to the 30S subunit of bacterial ribosomes, blocking access of aminoacyl-tRNA to the A-site of the ribosome. This inhibits peptide elongation and thus stops bacterial protein synthesis. Unlike aminoglycosides, tetracyclines do not cause misreading of mRNA and are bacteriostatic, not bactericidal.

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Classification

Tetracyclines are categorized based on their duration of action, which is primarily determined by lipid solubility and renal clearance:

1. Short-acting tetracyclines: Half-life 6–8 hours

   • Tetracycline

   • Oxytetracycline

2. Intermediate-acting:

   • Demeclocycline

3. Long-acting tetracyclines: Half-life 16–20 hours or more

   • Doxycycline

   • Minocycline

   • Tigecycline (glycylcycline derivative)

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Generic and Brand Name Examples

Generic Name	Common Brand Names
Tetracycline	Sumycin
Doxycycline	Vibramycin, Doryx, Monodox
Minocycline	Minocin, Solodyn
Tigecycline	Tygacil
Demeclocycline	Declomycin
Eravacycline	Xerava
Sarecycline	Seysara
Omadacycline	Nuzyra

Therapeutic Indications

Infectious Diseases

• Respiratory tract infections (e.g., Mycoplasma pneumoniae)

• Sexually transmitted infections (Chlamydia trachomatis)

• Rickettsial infections (e.g., Rocky Mountain spotted fever, typhus)

• Tick-borne diseases (Borrelia burgdorferi, Anaplasma)

• Cholera

• Brucellosis

• Plague (Yersinia pestis)

• Malaria prophylaxis and treatment (e.g., doxycycline)

• H. pylori infection (part of quadruple therapy)

• Acne vulgaris (due to Cutibacterium acnes)

Non-Infectious Uses

• Inflammatory acne and rosacea

• Rheumatoid arthritis (off-label)

• SIADH (demeclocycline induces nephrogenic diabetes insipidus)

• Periodontitis (sub-antimicrobial doxycycline)

• MMP inhibition in cancer (investigational)

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Pharmacokinetics

• Absorption: Well-absorbed orally (except tigecycline, given IV). Food can reduce absorption of older tetracyclines but not doxycycline or minocycline.

• Distribution: Widely distributed; good tissue penetration, including lungs, sinuses, prostate, skin; crosses placenta.

• Metabolism: Minimal hepatic metabolism for most; excretion varies.

• Elimination:

  • Tetracycline, oxytetracycline: renal

  • Doxycycline, minocycline: biliary/fecal (safe in renal impairment)

  • Tigecycline: hepatic metabolism and biliary excretion

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Adverse Effects

System Affected	Adverse Reactions
Gastrointestinal	Nausea, vomiting, diarrhea, esophagitis
Dermatological	Photosensitivity, rash, hyperpigmentation
Dental/Bone	Tooth discoloration, enamel hypoplasia, bone growth inhibition (especially in children <8 years)
Hepatic	Hepatotoxicity (especially with high doses or pregnancy)
Renal	Fanconi syndrome (expired tetracycline)
Vestibular	Dizziness, vertigo (minocycline)
Hypersensitivity	Urticaria, Stevens–Johnson syndrome (rare)
Others	Pseudotumor cerebri, benign intracranial hypertension

Contraindications

• Pregnancy (especially 2nd and 3rd trimesters) – risk of fetal skeletal and dental effects

• Children under 8 years of age – due to permanent teeth discoloration

• Severe hepatic impairment (especially for tigecycline)

• Known hypersensitivity to tetracycline class

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Precautions

• Administer with full glass of water and remain upright to reduce risk of esophagitis

• Avoid co-administration with antacids, calcium, magnesium, iron, or zinc, which chelate tetracyclines and reduce absorption

• Monitor liver function with prolonged therapy

• Use sun protection due to photosensitivity risk

• Adjust dosing for hepatic or renal dysfunction depending on agent

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Drug Interactions

Interacting Agent	Interaction Type / Result
Antacids/calcium/iron	↓ Absorption of tetracyclines (chelation)
Oral contraceptives	Possible ↓ efficacy (controversial, backup advised)
Retinoids (e.g., isotretinoin)	↑ Risk of intracranial hypertension
Warfarin	Potentiation of anticoagulant effect
Penicillin	Antagonistic effect (bacteriostatic vs. bactericidal)
Barbiturates/phenytoin	↓ Doxycycline levels (increased hepatic metabolism)

Resistance Mechanisms

Bacterial resistance to tetracyclines can occur via:

• Efflux pumps: Transport drug out of bacterial cell (e.g., tetA, tetK)

• Ribosomal protection proteins: Prevent binding to 30S subunit (e.g., tetM)

• Enzymatic inactivation: Rare mechanism

• Mutations in ribosomal genes: Less common

Newer agents like tigecycline, omadacycline, and eravacycline are designed to overcome common tetracycline resistance mechanisms.

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Clinical Considerations in Special Populations

Population	Clinical Consideration
Pregnancy	Contraindicated (Category D; risk of fetal damage)
Pediatrics	Avoid under 8 years old (tooth/bone effects)
Elderly	Monitor renal/liver function; doxycycline preferred
Hepatic impairment	Avoid or dose-reduce minocycline, tigecycline
Renal impairment	Avoid older tetracyclines; doxycycline is safe

Comparative Properties of Selected Tetracyclines

Drug	Half-life	Route	Renal Adjustment	Photosensitivity	CSF Penetration
Tetracycline	6–8 hrs	Oral	Yes	Yes	Poor
Doxycycline	16–22 hrs	Oral/IV	No	Yes	Moderate
Minocycline	16–18 hrs	Oral/IV	No	Yes	Good
Tigecycline	42 hrs	IV	No	Low	Good

Antimicrobial Spectrum

Pathogen Type	Coverage
Gram-positive cocci	Good (MSSA, MRSA with doxycycline)
Gram-negative rods	Moderate (limited for Pseudomonas)
Anaerobes	Some agents active (tigecycline)
Atypicals	Excellent (Chlamydia, Mycoplasma)
Rickettsiae	Excellent
Spirochetes	Good (Lyme disease, syphilis alternative)

Therapeutic Guidelines and Usage

• Acne: Doxycycline/minocycline 50–100 mg once or twice daily

• Chlamydia: Doxycycline 100 mg twice daily for 7 days

• Malaria prophylaxis: Doxycycline 100 mg daily starting 1–2 days before travel

• Rickettsial diseases: Doxycycline 100 mg twice daily for 7–14 days

• Periodontitis: Doxycycline sub-antimicrobial dose (20 mg BID)