Tetracyclines

Tetracyclines are broad-spectrum, bacteriostatic agents consisting of four cyclic rings. The group includes :

Tetracycline.
Oxytetracycline.
Demeclocycline.
Doxycycline.
Minocycline.
Glycylcycline : Tigecycline.

Mechanism of Action

The tetracyclines bind to the 30S ribosome and block the attachment of aminoacyl tRNA to the Acceptor (A) site on the mRNA-ribosome complex.

Mechanisms of entry into bacterial cells:

Energy dependent active transport, which pumps tetracyclines across the cytoplasmic membrane.
Gram-negative bacteria : Passive diffusion through porin channels.
More lipid-soluble members (Doxycycline, Minocycline) enter by passive diffusion also, hence increasing their potency.

Mechanism of Resistance

Decreased intracellular accumulation : There is decreased influx of the drug or acquisition of an energy-dependent efflux pathway.
Synthesis of a 'protection' protein that protects the ribosomal binding site, by displacing tetracycline from its target.
Cross-resistance : Incomplete, since, doxycycline and minocycline are effective in some resistant cases. However, when resistance is produced by ribosomal protection mechanism, doxycycline and minocycline may be ineffective, since the target site protected is same for all tetracyclines.

Antimicrobial Spectrum

Tetracyclines are broad-spectrum antibiotics, effective against all types of pathogens except, fungi and viruses. However, a lot of resistance has developed due to inadvertent and indiscriminate use.

High sensitivity

Few Streptococcus pyogenes, Staph. aureus (including MRSA) and Enterococci.
Most gram-positive bacilli : Clostridia and other anaerobes, Listeria, Corynebacteria, Propionibacterium acnes, B. anthracis.
Gram-negative bacteria : V. cholerae, Yersinia pestis, Yersinia enterocolitica, Campylobacter, Brucella, Pasteurella multocida, F. tularensis.
Spirochetes, including T. pallidum and Borrelia.
Rickettsiae and Chlamydiae.

Moderate sensitivity

Mycoplasma and Actinomyces.
Protozoa like Entamoeba histolytica (inhibited at high concentrations).

Insensitive / Developed resistance

Streptococcus pneumoniae.
Mycobacteria, except M. leprae (sensitive to minocycline).
H. influenzae.
Enterobacteriaceae.
Pseudomonas aeruginosa, Proteus, Klebsiella, Salmonella typhi and many Bacteroides fragilis.

Pharmacokinetics

Absorption

Oral absorption of most tetracyclines is incomplete, however, doxycycline and minocycline are almost completely absorbed.
Tetracyclines have chelating property and form insoluble and unabsorbable complexes with calcium and other metals. Hence, their absorption is impaired by concurrent ingestion of dairy products, calcium, magnesium, iron or zinc salts, bismuth subsalicylate, non-systemic antacids (eg. aluminium hydroxide gels) and sucralfate.
Absorption is better if taken empty stomach. However, food (including dairy products) does not interfere with the absorption of doxycycline and minocycline.

Distribution

Tetracyclines are widely distributed in the body (Volume of distribution more than 1 L/kg).
Accumulate in the reticuloendothelial cells of the liver, spleen and bone marrow and in bone, dentin and enamel of unerupted teeth.
Minocycline accumulates in body fat, due to its high lipid solubility.
Crosses the placenta and enter fetal circulation and amniotic fluid.
Relatively high concentrations are found in breast milk.

Elimination

Most tetracyclines are primarily eliminated by kidney and excreted in urine (glomerular filtration). Hence, dose has to be reduced in case of renal failure.
Exception : Doxycycline (Does not accumulate significantly in patients with renal failure, hence safe in such cases).

Indications

Rickettsial infections (life saving) : Rocky mountain spotted fever, recrudescent epidemic typhus, scrub typhus, rickettsial pox and Q fever.
Chlamydia : Chlamydial nonspecific urethritis / endocervicitis, Lymphogranuloma venerum, Chlamydia pneumoniae.
Atypical pneumonia (Mycoplasma pneumoniae).
Granuloma inguinale (Calymmatobacterium granulomatis).
Trachoma.
Primary, secondary or latent syphilis (Non-pregnant, penicillin-allergic patients).
Anthrax .
Brucellosis.
Tularemia (Ulceroglandular and typhoidal types).
Cholera.
Relapsing fever (Borrelia recurrentis).
Plague (Bubonic and pneumonic plague).

Administration and Dosage

Oral administration : Tetracyclines should be administered 2 hours before or 2 hours after meals and other drugs that interfere with their absorption.

Tetracycline
- Adults : 1-2 g/day.
- Children (more than 8 yrs) : 25-5- mg/kg/day in 2-4 divided doses.
Doxycycline
- Adults : 100 mg BD (12 hrly) on the first day, then 100mg OD or twice daily(in severe infection).
- Children (above 8 years) : 4-5 mg/kg/day in two divided the first day, then 2-2.5 mg/kg once or twice daily.
Minocycline
- Adults : 200mg initially, followed by 100 mg every 12 hr.
- Children : 4mg/kg initially followed by 2mg/kg every 12 hr.

Parenteral administration : Indicated in patients severe illness and unable to ingest medication or when the drug causes nausea and vomiting.

Tetracyclines should be given intravenously and not intramuscularly because of local irritation and poor absorption after IM injection.

Doxycycline (preferred)
- Adults : 200mg in one or two infusions on the first day, then, 100mg once or twice daily.
- Children (less than 45 kg) : 4.4mg/kg on the first day, then, 2.2mg/kg/day.
Minocycline
- Adults : 200mg, followed by 100mg every 12 hrs.
- Children (Above 8 yrs) : Initial dose of 4mg//kg, followed by 2mg/kg every 12 hrs.
- Each 100mg must be diluted with 500-1000ml of compatible fluid and slowly infused over 6 hrs to minimise toxicity.

Topical Application

Not recommended, except for local use in the eye.
Minocycline sustained-release microspheres : Used as sub-gingival administration in patients with adult periodontitis.

Adverse Effects

Gastrointestinal irritation, epigastric pain, nausea, vomiting and diarrhoea.
Oesophagitis and oesophageal ulceration (due to release of the drug from capsules in the oesophagus during swallowing).
Photosensitivity.
Hepatic toxicity (Fatty infiltration of liver and jaundice) : When 2g or more administered per day parenterally.
May aggravate azotemia in patients with renal disease (because of their catabolic effects).
Demeclocycline may cause Nephrogenic Diabetes Insipidus. (This effect has been exploited to treat inappropriate secretion of anti-diuretic hormone.)
Fanconi syndrome : Seen in patients taking outdated tetracycline (Degradation products - epitetracycline, anhydrotetracycline and epianhydrotetracycline damage the proximal tubules).
Pseudomembranous colitis : Potentially life threatening complication caused by the overgrowth of Clostridium difficile.
Permanent brown discolouration of teeth : Tetracyclines administered during pregnancy and in children between 2 months and 5 years (Calcium-tetracycline chelate gets deposited in developing teeth and bone).

Points to Note

Tetracyclines are not harmful to host cells since,
- The carrier involved in active transport of tetracyclines is absent in host cells.
- Protein synthesising apparatus of host cells is less susceptible to tetracyclines.
Tetracyclines should not be used during pregnancy, lactation and in children.
Tetracyclines should be avoided in patients on diuretics (blood urea may rise in such patients) and should be cautiously used in renal or hepatic insufficiency.
Preparations should never be used beyond their expiry date.
Do not mix injectable tetracyclines with penicillin (causes inactivation).

References

Essentials of Medical Pharmacology 8th Edition (K.D. Tripathi)-Jaypee Brothers Medical Publishers (P) Ltd.
Laurence L. Brunton - Goodman & Gilman's Manual of Pharmacology and Therapeutics-McGraw-Hill Medical (2008).

*This article is an excerpt from the above mentioned books and Medical Sutras does not make any ownership or affiliation claims.