Tetracyclines

Tetracyclines (doxycycline, minocycline, tetracycline, oxytetracycline, lymecycline, demeclocycline, sarecycline) are broad-spectrum bacteriostatic protein synthesis inhibitors with activity against intracellular and atypical organisms, rickettsiae, spirochaetes and many Gram-positive and Gram-negative bacteria. Doxycycline is by far the most used member and is the first-line drug for several tropical infections.

Mechanism. Reversible binding to the 30S ribosomal subunit blocks attachment of aminoacyl-tRNA to the ribosomal A site. Activity is bacteriostatic; the effect correlates with AUC to MIC ratio.

Pharmacokinetics. Doxycycline and minocycline absorb almost completely orally (over 90 percent), unaffected by food but severely reduced by divalent and trivalent cations. Half-lives are 16 to 22 hours (doxycycline) and 11 to 22 hours (minocycline). Doxycycline is eliminated by non-renal routes (faeces, gut) and needs no renal adjustment; tetracycline is renally cleared and accumulates in renal failure.

Resistance. Efflux pumps (tet(A) to tet(E), tet(K)) and ribosomal protection proteins (tet(M)); cross-resistance within the class, though minocycline and the glycylcyclines may overcome efflux.

• Doxycycline: twice-daily or once-daily oral and IV forms; most widely used.
• Minocycline: more lipophilic, CNS penetration, activity against some MRSA and Acinetobacter; vestibular side effects, hyperpigmentation, drug-induced lupus and DRESS.
• Tetracycline, oxytetracycline: four times daily; older agents, now mainly for acne, Helicobacter regimens and where doxycycline is not stocked.
• Demeclocycline: causes nephrogenic diabetes insipidus and is used off-label for chronic SIADH (usually 600 to 1200 mg daily in divided doses, with renal monitoring).

Adult regimens (doxycycline unless stated).

• General dose: 100 mg orally or IV every 12 hours (some regimens use a 200 mg first dose).
• Atypical pneumonia, exacerbation of COPD: 100 mg every 12 hours for 5 to 7 days.
• Chlamydial urethritis and cervicitis: 100 mg every 12 hours for 7 days. Pelvic inflammatory disease: 100 mg every 12 hours for 14 days with other agents.
• Syphilis in penicillin allergy: 100 mg every 12 hours for 14 days (early) or 28 days (late latent).
• Rickettsial infection, scrub typhus, Q fever, leptospirosis, Lyme disease: 100 mg every 12 hours for 7 days (scrub typhus and rickettsia, continued until afebrile for 3 days), 14 to 21 days (Lyme).
• Brucellosis: 100 mg every 12 hours for 6 weeks with rifampicin or an aminoglycoside.
• Cholera: 300 mg orally once.
• Malaria: prophylaxis 100 mg daily, starting 1 to 2 days before travel and continued 4 weeks after; treatment adjunct 100 mg every 12 hours for 7 days with quinine or artesunate.
• Tetracycline 250 to 500 mg every 6 hours; minocycline 100 mg every 12 hours.
• Children over 8 years: doxycycline 2.2 mg/kg every 12 hours (maximum 100 mg each dose). Under 8 years, doxycycline for 21 days or less is used for rickettsial infection and other serious indications because dental staining risk is low.

Selection. First line for rickettsial infection, scrub typhus, leptospirosis (mild), Lyme disease, chlamydia, brucellosis and cholera alternatives. Taken with a full glass of water, sitting upright, with at least 2 hours between doses and iron, calcium, antacids, zinc or magnesium.

Contraindications. Hypersensitivity; pregnancy (second and third trimester: foetal tooth and bone effects, maternal hepatotoxicity); children under 8 years except short courses for serious indications. Outdated tetracycline preparations are avoided in renal failure.

Serious effects. Oesophageal ulceration (severe pain on swallowing); photosensitivity; raised intracranial pressure (papilloedema, headache), especially with isotretinoin or in young women with obesity; hepatotoxicity; Clostridioides difficile infection; DRESS and Stevens-Johnson syndrome; tooth discolouration; vestibular toxicity (minocycline); Fanconi syndrome with degraded tetracycline.

Interactions. Cations reduce absorption. Carbamazepine, phenytoin and rifampicin lower doxycycline levels. Warfarin is potentiated. Isotretinoin and other retinoids add intracranial hypertension risk. Methotrexate and ciclosporin levels may rise.

Monitoring. Liver tests with long courses; blood pressure and visual symptoms if headache; sun protection advice.

Special groups. Pregnancy: avoided; where needed (for example severe rickettsial infection), the benefit justifies it. Breastfeeding: short courses are acceptable. Renal impairment: doxycycline needs no change. Hepatic impairment: use with caution. Older adults: oesophagitis risk.