Tetracyclines

TETRACYCLINES

The tetracyclines are a group of broad-spectrum antibiotics that are declining in use as a result of increasing bacterial resistance. Despite that, they remain important antibiotics for several dangerous, but relatively rare, infections due to chlamydia (e.g. trachoma), rickettsia (e.g. typhus and Q-fever) and spirochaetes (e.g. Lyme disease) as well as those caused by ‘typical’ bacteria (e.g. brucellosis and bubonic plague). They also represent useful alternatives to macrolides (see section 4 of this chapter) and to β-lactams (particularly in cases of allergy) for the treatment of more common infections, including those of the respiratory tract.

The tetracyclines (Figure 11.7) were first developed during the 1940s and 1950s and several that are still in use date from that time, e.g. tetracycline itself, oxytetracycline and chlortetracycline. Doxycycline and minocycline are more potent semisynthetic analogues discovered in 1966 and 1972 respectively, after which there were no significant developments until the introduction, in 2005, of tigecycline (a glycylglycine derivative), which is generally more potent again than other tetracyclines and maintains activity against some organisms that have become resistant to earlier members of the group.

Although the tetracyclines can exhibit bactericidal activity by inhibiting ribosome function at concentrations that might be used in the laboratory, they are bacteristatic at concentrations that can safely be achieved in the body. They are active against Gram-positive bacteria, although many strains of Staph. aureus have become resistant to all but tigecycline which, as a consequence, is of value in the treatment of MRSA infections. Many Gram-negative species are also sensitive to tetracyclines, and although the proportion of strains responding to treatment has significantly diminished in recent years there are substantial geographical variations in resistance patterns; Ps. aeruginosa and Proteus species are normally resistant. In addition to the infections mentioned above, tetracyclines are prescribed for the treatment of acne, various genital infections, the eradication of Helicobacter pylori in gastric and peptic ulcer disease (as part of a multidrug regimen) and, in the case of doxycycline particularly, for the prophylaxis of drug-resistant Plasmodium falciparum malaria.

Resistance to the tetracyclines develops relatively slowly, but there is cross-resistance, i.e. an organism resistant to one member is usually resistant to all other members of this group, but there are excep tions: tigecycline (mentioned above), and tetracyclineresistant Staph. aureus strains may still be sensitive to minocycline. Superinfection (‘overgrowth’) with naturally tetracycline-resistant organisms, for example Candida albicans and other yeasts, affecting the mouth, upper respiratory tract or gastrointestinal tract, may occur as a result of the suppression of tetracyclinesusceptible microorganisms.

Tetracyclines are absorbed from the gastrointestinal tract and oral products are the only form in which they are currently available in the UK, although ophthalmic, topical and injectable products have been used in the past and some are still available in other countries. Absorption of tetracyclines is inhibited by food, antacids, milk or products containing dior trivalent cations, so tetracycline, oxytetracycline and chlortetracycline have to be administered four times a day in order to maintain adequate tissue concentrations. Such impaired absorption is much less evident in the more recently developed drugs, and partly as a consequence of both this improvement and of extended half-lives, lymecycline, minocycline and tigecycline are administered twice daily, and doxycycline just once. The newer tetracyclines are also more lipophilic than the early ones, so doxycycline, and to an even greater extent minocycline, exhibit good tissue distribution and achieve concentrations in the biliary tract, liver, kidneys and other organs which may substantially exceed those in the blood.

Dose-dependent nausea and vomiting are the most common side effects, and diarrhoea may arise as a consequence of alterations in the bacterial flora of the colon. The ability to chelate with calcium results in tetracyclines being deposited in bones and teeth, and precludes their administration to children younger than 12 years or to women in late pregnancy. Their use in patients with poor kidney function is also contraindicated because most of the tetracyclines accumulate in this situation; again, doxycycline and minocycline are exceptions.