Tetracyclines

TETRACYCLINES

Structure and Mechanism of Action

Although all tetracyclines have a similar mechanism of action, they have different chemical structures and are produced by different species of Streptomyces. In addi-tion, structural analogues of these compounds have been synthesized to improve pharmacokinetic proper-ties and antimicrobial activity. While several biological processes in the bacterial cells are modified by the tetra-cyclines, their primary mode of action is inhibition of protein synthesis. Tetracyclines bind to the 30S ribosome and thereby prevent the binding of aminoacyl transfer RNA (tRNA) to the A site (acceptor site) on the 50S ri-bosomal unit. The tetracyclines affect both eukaryotic and prokaryotic cells but are selectively toxic for bacte-ria, because they readily penetrate microbial membranes and accumulate in the cytoplasm through an energy-dependent tetracycline transport system that is absent from mammalian cells.

Resistance is related largely to changes in cell per-meability and a resultant decreased accumulation of drug due to increased efflux from the cell by an energy-dependent mechanism. Other mechanisms, such as pro-duction of a protein that alters the interaction of tetra-cycline with the ribosome and enzymatic inactivation of the drug, have been reported.

Antibacterial Spectrum

The tetracyclines display broad-spectrum activity and are effective against both gram-positive and gram-negative bacteria, including Rickettsia, Coxiella, Mycoplasma, and Chlamydia spp.. Tetracycline resistance has increased among pneumococci and gonococci, which limits their use in the treatment of infections caused by these organisms.

Although several congeners of the tetracyclines are available, they all have a similar spectrum of in vitro ac-tivity. Minocycline is somewhat more active and oxytet-racycline and tetracycline are somewhat less active than other members of this group.

Absorption, Distribution, Metabolism, and Excretion

These antibiotics are partially absorbed from the stom-ach and upper gastrointestinal tract. Food impairs ab-sorption of all tetracyclines except doxycycline and minocycline. Absorption of doxycycline and minocy-cline is improved with food. Since the tetracyclines form insoluble chelates with calcium (such as are found in many antacids), magnesium, and other metal ions, their simultaneous administration with milk (calcium), mag-nesium hydroxide, aluminum hydroxide, or iron will in-terfere with absorption. Because some of the tetracy-clines are not completely absorbed, any drug remaining in the intestine may inhibit sensitive intestinal microor-ganisms and alter the normal intestinal flora.

The tetracyclines are distributed throughout body tissues and fluids in concentrations that reflect the lipid solubility of each individual agent. Minocycline and doxycycline are the most lipid soluble, while oxytetracy-cline is the least lipid soluble. The tetracyclines pene-trate (but somewhat unpredictably) the uninflamed meninges and cross the placental barrier. Peak serum levels are reached approximately 2 hours after oral ad-ministration; cerebrospinal fluid (CSF) levels are only one-fourth those of plasma.

The various congeners differ in their half-lives and their protein binding ability (Table 47.1). Significant dif-ferences in serum half-life allow the grouping of the tetracyclines into subclasses: short acting (tetracycline, chlortetracycline, and oxytetracycline), intermediate act-ing (demeclocycline and methacycline), and long acting (minocycline and doxycycline).

The tetracyclines are metabolized in the liver and are concentrated in the bile. Bile concentrations can be up to five times those of the plasma. Doxycycline, minocycline, and chlortetracycline are excreted prima-

rily in the feces. The other tetracyclines are eliminated primarily in the urine by glomerular filtration. Obvi-ously, these tetracyclines have greater urinary antibac-terial activity than those (e.g., doxycycline) that are ex-creted by nonrenal mechanisms.

Clinical Uses

There is little difference in clinical response among the various tetracyclines. The selection of an agent, therefore, is based on tolerance, ease of administration, and cost. The restriction of their use in pregnancy and in patients under the age of 8 years applies to all preparations.

Two tetracyclines have sufficiently distinctive fea-tures to warrant separate mention. Doxycycline, with its longer half-life and lack of nephrotoxicity, is a popular choice for patients with preexisting renal disease or those who are at risk for developing renal insufficiency. The lack of nephrotoxicity is related mainly to biliary excretion, which is the primary route of doxycycline elimination. Doxycycline is the preferred parenteral tetracycline. Doxycycline is a potential first-line agent in the prophylaxis of anthrax after exposure. Doxycycline is the treatment of choice for the primary stage of Lyme disease in adults and children older than 8 years.

Minocycline is an effective alternative to rifampin for eradication of meningococci, including sulfonamide-resistant strains, from the nasopharynx. However, the high incidence of dose-related vestibular side effects renders it less acceptable. Although minocycline has good in vitro activity against Nocardia spp., further studies are necessary to confirm its clinical efficacy.

The tetracyclines are still the drugs of choice for treatment of cholera, diseases caused by Rickettsia and Coxiella, granuloma inguinale, relapsing fever, the chlamydial diseases (trachoma, lymphogranuloma venereum, and psittacosis), and nonspecific urethritis. 

They are also effective in the treatment of brucellosis, tularemia, and infections caused by Pasteurella and Mycoplasma spp., although other agents may be equally effective. Tetracyclines are clinically effective in acne because of their antioxidant effect on the degranulated neutrophils in the comedone acidic contents (in which long-term low-dose therapy is popular). Mild to moder-ate attacks of pelvic inflammatory disease often re-spond to tetracycline, probably as a result of the drug’s action on anaerobic bacteria and chlamydia.

Tetracyclines no longer can be entirely relied on in the treatment of streptococcal infections; up to 40% of Streptococcus pyogenes and 10% of Streptococcus pneu-moniae are resistant.

Adverse Effects

Oral administration can cause nausea, vomiting, epigas-tric burning, stomatitis, and glossitis, and an intravenous injection can cause phlebitis. When given over long pe-riods, use of these agents can result in a negative nitro-gen balance, which may lead to elevated blood urea ni-trogen. Hepatotoxicity occurs infrequently but is particularly severe during pregnancy, when the combi-nation of uremia and increasing jaundice can be fatal. In addition, these antibiotics are occasionally nephrotoxic and should not be administered with other potentially nephrotoxic drugs. Staining of both the deciduous and permanent teeth and retardation of bone growth can occur if tetracyclines are administered after the fourth month of gestation or if they are given to children less than 8 years of age.

Photosensitivity, observed as abnormal sunburn reac-tion, is particularly associated with demeclocycline and doxycycline administration. Superinfection may result in oral, anogenital, and intestinal Candida albicans infec-tions, whereas Staphylococcus aureus or Clostridium dif-ficile overgrowth may cause enterocolitis. Minocycline can produce vertigo.

Minocycline is frequently used in the treatment of chronic facial dermatoses. Increased usage has resulted in local skin pigmentation, particularly at sites of previ-ous tissue trauma that is unrelated to the photosensiti-zation phenomenon characteristic of this class of drug. This effect does not appear to be dose dependent and usually resolves in months to years following drug dis-continuation.

Other significant side effects of minocycline may make it unsuitable for some light-skinned patients. In particular, dark bone pigmentation is severe enough to be visible through the mucosae of the alveolar ridges in the mouth and other areas where bone directly adheres to skin (black bone disease). Thyroid staining is visible through the overlying skin of the neck but does not af-fect the endocrine function of the gland.

Pulmonary eosinophilic syndrome, characterized by extreme hypoxemia, eosinophilia, interstitial pneu-monitis, hilar lymphadenopathy, and pleural effusions, can be severe and can occur with as little as 7 to 9 days of therapy with the tetracyclines. In severe cases steroid therapy is required, but the outcome following drug dis-continuation is nearly always good.

Pseudotumor cerebri is another potential complica-tion of chronic use of these agents, particularly in indi-viduals treated for severe cystic acne with simultaneous use of isotretinoin. This complication can be induced within several days of initiation of therapy and usually resolves with cessation of treatment.

Chronic use always predisposes to the development of fungal esophagitis, which may be so severe as to re-quire treatment with antifungal therapy. Prompt recog-nition of dysphagia and cessation of treatment are usu-ally curative.