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Key drug.
The two tetracyclines seen in primary care are tetracycline and doxycycline. Doxycycline is by far the most commonly used tetracycline. Tetracyclines are active against a wide range of aerobic and gram-positive and gram-negative bacteria (e.g., Haemophilus ducreyi, Yersinia pestis). Most gram-positive bacteria are now resistant to tetracyclines. These are not the drugs of choice for Streptococcus or Staphylococcus. Their greatest usefulness is against rickettsia, mycoplasma, protozoa, and chlamydia. Tetracyclines are not active against fungi or viruses. Tetracyclines are being used increasingly for malaria as mefloquine-resistant strains are increasing. They have few major side effects, except on the teeth of children and pregnant women, and possibly diarrhea, which can be a symptom of superinfection or a side effect. In the 1950s, tetracyclines were discovered to be produced by Streptomyces aureofaciens.
Therapeutic Overview
Allergies are not common. Anaphylaxis, urticaria, periorbital edema, fixed drug eruptions, and morbilliform rashes may occur. A systemic lupus erythematosus–like syndrome has been seen, along with positive antinuclear antibody.
Resistance
Resistance to tetracyclines is plasmid mediated and occurs via decreased influx into the cell, decreased access to the ribosome, and enzymatic inactivation. Campylobacter and Shigella have become largely resistant. A total of 15% to 60% of pneumococci have become resistant. No known protozoa, chlamydia, or rickettsia have become resistant.
All of the tetracyclines exhibit similar antimicrobial activity, and cross-resistance is common. Resistance has reduced their usefulness in recent years. Another major restriction is the contraindication for use in children younger than 8 years old and in pregnant women. If used in children or in pregnant women, the drug may permanently stain teeth. The severity of staining is determined by timing, duration, and the form of tetracycline administered. The traditional method used to repair the staining required aggressive tooth preparation. Recently, conservative preparations for porcelain veneer have been used with success.
Mechanism of Action
The basic tetracycline structure is a hydronaphthacene nucleus that contains four fused six-carbon rings. Tetracyclines differ in terms of substitutions on the fifth, sixth, or seventh position of the basic tetracycline structure. These substitutions affect lipid solubility, serum half-life, and the effect that food has on bioavailability of the drug.
The tetracyclines are bacteriostatic antibiotics. Their mechanism of action is to inhibit protein synthesis in the susceptible organism by binding to the 30S ribosome subunit, thereby impeding the binding of aminoacyl tRNA to the receptor site on the messenger RNA ribosome complex. Tetracyclines also may reversibly bind to 50S ribosomal subunits and may alter cytoplasmic membranes of susceptible organisms, resulting in leakage of cytosolic nucleotides. This action requires active microbial growth that distinguishes tetracyclines as bacteriostatic rather than bactericidal agents.
Treatment Principles
Little difference in microbial activity is noted between the different tetracyclines. Tetracyclines are wide-spectrum antibiotics that are useful for empirical therapy. They are one of the drugs of first choice for acute bacterial exacerbation of COPD, chlamydia, and rickettsial infection, and they provide a second-line consideration for many other infections, especially in a patient with allergy to other antibiotics.
The choice between tetracyclines is made by determination of drug characteristics. Doxycycline and minocycline are the two most commonly used tetracyclines. Most tetracyclines must not be taken with milk or antacids; however, minocycline and doxycycline do not have this complicating factor, so it is easier to get the patient to take them correctly. Also, doxycycline has a longer half-life than tetracycline. Doxycycline produces less gastrointestinal disturbance than the other tetracyclines, although it can cause diarrhea. Overall, doxycycline is the most useful tetracycline in primary care; however, it is imperative that pregnant women not take tetracyclines.
Nonantibiotic actions of tetracyclines result in antiinflammatory processes, immunosuppression, inhibition of lipase and collagenase, enhancement of gingival fibroblast cell attachment, and wound healing.
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