Tetracyclines

Chemical Structure & Classification

Tetracyclines are a family of antibiotics built around a four-ring (naphthacene) core with various substituents that distinguish individual members. Members in clinical use include:

Drug	Route	Half-life	Dosing	Notes
Tetracycline	Oral	~8 h	Every 6 h	Prototype; renal elimination
Doxycycline	Oral/IV	~18 h	Every 12 h	Nonrenal; minimal food interaction
Minocycline	Oral/IV	~16 h	Every 12 h	Vestibular toxicity; hepatic metabolism
Tigecycline	IV	~42 h	q12h (50 mg)	Glycylcycline; overcomes resistance
Eravacycline	IV	-	q12h (1 mg/kg)	Fluorocycline; broadest gram-negative coverage
Omadacycline	Oral/IV	-	Once daily	Aminomethylcycline; empty stomach required

Mechanism of Action

Tetracyclines inhibit bacterial protein synthesis by binding reversibly to the 30S ribosomal subunit, blocking the A (acceptor) site and preventing aminoacyl-tRNA from docking on the mRNA-ribosome complex. The result is arrest of peptide chain elongation.

Tetracycline mechanism - blocks aminoacyl-tRNA from entering the A site on the 30S ribosomal subunit

Figure: Tetracyclines bind the 30S subunit and block tRNA binding to the A site, halting protein synthesis (Goodman & Gilman's)

Entry into gram-negative bacteria occurs via passive diffusion through porin channels in the outer membrane and by active transport across the cytoplasmic membrane.

Effect: Bacteriostatic (bactericidal in high doses/specific organisms)

Antimicrobial Spectrum

Tetracyclines are intrinsically more active against gram-positives than gram-negatives (gram-negatives efflux them more effectively):

Gram-positive: S. pyogenes, S. pneumoniae (PCN-sensitive), MSSA, MRSA (doxycycline/minocycline)
Gram-negative: H. influenzae, Vibrio cholerae, V. vulnificus, Campylobacter, H. pylori, Yersinia pestis, Francisella tularensis, Brucella spp., Pasteurella multocida; intrinsic resistance in Pseudomonas, Proteus
Atypicals: Mycoplasma pneumoniae, Chlamydia spp., Legionella spp., Ureaplasma, Coxiella burnetii
Rickettsiae: Rickettsia, Ehrlichia, Anaplasma
Spirochetes: Borrelia burgdorferi (Lyme), Treponema pallidum (syphilis), Borrelia recurrentis
Other: Plasmodium spp., Bacillus anthracis, nontuberculous mycobacteria (M. marinum)

Clinical Indications

First-line uses

Chlamydia, lymphogranuloma venereum, granuloma inguinale
Rickettsial diseases (Rocky Mountain spotted fever, ehrlichiosis)
Lyme disease (Borrelia infections)
Community-acquired pneumonia (doxycycline, outpatient)
Tularemia (mild to moderate), plague (Yersinia pestis), brucellosis
Purulent skin/soft-tissue infections and MRSA SSTIs
Acne vulgaris
H. pylori eradication (tetracycline + bismuth + metronidazole + PPI)
Malaria prophylaxis and treatment (doxycycline with quinine for chloroquine-resistant strains)
M. marinum infections

Alternative/second-line uses

Syphilis (penicillin-allergic patients)
Anthrax, actinomycosis, animal bites (Pasteurella)
Cholera, Nocardia (minocycline + sulfonamide)
SIADH (demeclocycline - exploits nephrogenic DI side effect)

(Fitzpatrick's Dermatology; Goodman & Gilman's; Goldman-Cecil Medicine)

Pharmacokinetics

Oral absorption: Tetracycline ~60-70%; doxycycline ~93% (less affected by food/cations than others)
Chelation: All oral tetracyclines are chelated by divalent/trivalent cations (Ca²⁺, Mg²⁺, Al³⁺, Fe²⁺) - avoid dairy, antacids, iron supplements (space by 2-4 h)
Distribution: Wide; crosses placenta; concentrates in liver, bone, teeth
Elimination:
- Tetracycline, demeclocycline: primarily renal - dose-adjust in renal failure
- Doxycycline, omadacycline: biliary + renal (no dose adjustment in renal failure)
- Minocycline: extensively hepatically metabolized
- Tigecycline, eravacycline: mostly excreted unchanged; dose-adjust in severe hepatic impairment

(Katzung's Basic & Clinical Pharmacology, 16e; Goodman & Gilman's)

Resistance Mechanisms

Three mechanisms (frequently plasmid-mediated, often inducible):

Active efflux pumps - the most common; Tet(A-E) in gram-negatives efflux tetracycline, doxycycline, minocycline; Tet(K) in staphylococci effluxes tetracycline only. Tigecycline, eravacycline, omadacycline are NOT substrates for most efflux pumps.
Ribosomal protection proteins - Tet(M) binds the tetracycline-ribosome complex and dislodges the drug, restoring protein synthesis. Confers cross-resistance to tetracycline, doxycycline, and minocycline but NOT to tigecycline/eravacycline/omadacycline (bulky substituents sterically block Tet(M) binding).
Enzymatic inactivation - uncommon; plasmid-encoded modification enzyme; can confer resistance to newer agents.

Intrinsic resistance: Pseudomonas aeruginosa and Proteus spp. are intrinsically resistant due to chromosomally encoded multidrug efflux pumps - this includes tigecycline, eravacycline, and omadacycline.

(Katzung 16e; Harrison's Principles of Internal Medicine 22e; Tietz Textbook of Laboratory Medicine)

Adverse Effects

Category	Effect
GI	Nausea, vomiting, epigastric discomfort, diarrhea; esophagitis/ulcers (take with full glass of water, remain upright)
Photosensitivity	Especially doxycycline; onycholysis; sunscreen required
Teeth/bone	Permanent brown discoloration of teeth in children <8 years; depressed bone growth; deposition in calcifying tissue
Hepatotoxicity	High-dose IV in renal failure or pregnancy; fatty liver
Renal/antianabolic	Aggravates azotemia in renal failure; avoid (except doxycycline/minocycline) in renal impairment; Fanconi syndrome with outdated tetracycline
Vestibular	Dizziness, vertigo, tinnitus - particularly minocycline
C. difficile colitis	Class effect; also Candida vaginitis
Tigecycline	Increased all-cause mortality (FDA warning from pooled clinical trial data)

Contraindications & Precautions

Pregnancy and lactation - dental/bone effects on fetus/infant
Children <8 years old - tooth discoloration (exception: compelling indications like Rocky Mountain spotted fever)
Renal failure - use doxycycline/minocycline if tetracycline class required
Drug interactions:
- Divalent/trivalent cations (food, dairy, antacids, iron, bismuth) - impair absorption
- Phenytoin, carbamazepine, barbiturates, alcohol - increase doxycycline metabolism (reduces serum levels)
- Digoxin, lithium, warfarin - tetracyclines increase serum levels
- Methoxyflurane anesthesia - combined nephrotoxicity
- Oral contraceptives - theoretical decreased efficacy (GI flora alteration)

(Fitzpatrick's Dermatology 2e; Goodman & Gilman's 14e; Goldman-Cecil Medicine)

Newer Tetracycline Derivatives (3rd/4th Generation)

These were engineered specifically to overcome resistance:

Tigecycline (glycylcycline): IV only; overcomes both efflux and ribosomal protection; very broad spectrum including MRSA, VRE, anaerobes, MDR gram-negatives; FDA warning for increased mortality; not useful for UTIs or bacteremia (poor urinary/serum levels)
Eravacycline (fluorocycline): IV; twice daily; similar profile to tigecycline; nausea the main side effect
Omadacycline (aminomethylcycline): Oral AND IV; once daily; requires empty stomach; good for CAP and SSTIs; promising safety profile

All three retain activity against Tet(M)- and efflux pump-resistant organisms but are still ineffective against Pseudomonas and Proteus.

Sources: Goodman & Gilman's Pharmacological Basis of Therapeutics; Katzung's Basic & Clinical Pharmacology, 16e; Harrison's Principles of Internal Medicine, 22e (2025); Fitzpatrick's Dermatology; Goldman-Cecil Medicine

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