Tetracyclines

TETRACYCLINES

All of the tetracyclines have the basic structure shown below:

Free tetracyclines are crystalline amphoteric substances of low solubility. They are available as hydrochlorides, which are more soluble. Such solutions are acid and, with the exception of chlortetracycline, fairly stable. Tetracyclines chelate divalent metal ions, which can interfere with their absorption and activity. A newly approved tetracycline analog, tigecycline, is a glycylcycline and a semisynthetic derivative of minocycline.

Mechanism of Action & Antimicrobial Activity

Tetracyclines are broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis. Tetracyclines enter microorganisms in part by passive diffusion and in part by an energy-dependent process of active transport. Susceptible organisms concentrate the drug intracellularly. Once inside the cell, tetracyclines bind revers-ibly to the 30S subunit of the bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex (Figure 44–1). This prevents addition of amino acids to the growing peptide.

Tetracyclines are active against many gram-positive and gram-negative bacteria, including certain anaerobes, rickettsiae, chla-mydiae, and mycoplasmas. The antibacterial activities of most tetracyclines are similar except that tetracycline-resistant strains may be susceptible to doxycycline, minocycline, and tigecycline, all of which are poor substrates for the efflux pump that mediates resistance. Differences in clinical efficacy for susceptible organisms are minor and attributable largely to features of absorption, distri-bution, and excretion of individual drugs.

Resistance

Three mechanisms of resistance to tetracycline analogs have been described: (1) impaired influx or increased efflux by an active trans-port protein pump; (2) ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome; and enzymatic inactivation. The most important of these are produc-tion of an efflux pump and ribosomal protection. Tet(AE) efflux pump-expressing gram-negative species are resistant to the older tetracyclines, doxycycline, and minocycline. They are susceptible, however, to tigecycline, which is not a substrate of these pumps. Similarly, the Tet(K) efflux pump of staphylococci confers resistance to tetracycline, but not to doxycycline, minocycline, or tigecycline, none of which are pump substrates. The Tet(M) ribosomal protection protein expressed by gram-positives produces resistance to tetracycline, doxycycline, and minocycline, but not to tigecycline, which because of its bulky t-butylglycylamido substituent, has a steric hindrance effect on Tet(M) binding to the ribosome. Tigecycline is a substrate of the chromosomally encoded multidrug efflux pumps of Proteus sp and Pseudomonas aeruginosa, accounting for their intrinsic resistance to alltetracyclines including tigecycline.

Pharmacokinetics

Tetracyclines differ in their absorption after oral administration and in their elimination. Absorption after oral administration is approximately 30% for chlortetracycline; 60–70% for tetracycline, oxytetracycline, demeclocycline, and methacycline; and 95–100% for doxycycline and minocycline. Tigecycline is poorly absorbed orally and must be administered intravenously. A portion of an orally administered dose of tetracycline remains in the gut lumen, alters intestinal flora, and is excreted in the feces. Absorption occurs mainly in the upper small intestine and is impaired by food (except doxycycline and minocycline); by divalent cations (Ca²⁺, Mg²⁺, Fe²⁺) or Al³⁺; by dairy products and antacids, which contain mul-tivalent cations; and by alkaline pH. Specially buffered tetracycline solutions are formulated for intravenous administration.

Tetracyclines are 40–80% bound by serum proteins. Oral dosages of 500 mg every 6 hours of tetracycline hydrochloride or oxytetracycline produce peak blood levels of 4–6 mcg/mL. Intravenously injected tetracyclines give somewhat higher levels, but only temporarily. Peak levels of 2–4 mcg/mL are achieved with a 200-mg dose of doxycycline or minocycline. Steady-state peak serum concentrations of tigecycline are 0.6 mcg/mL at the standard dosage. Tetracyclines are distributed widely to tissues and body fluids except for cerebrospinal fluid, where concentrations are 10–25% of those in serum. Minocycline reaches very high concen-trations in tears and saliva, which makes it useful for eradication of the meningococcal carrier state. Tetracyclines cross the placenta to reach the fetus and are also excreted in milk. As a result of chelation with calcium, tetracyclines are bound to—and damage—growing bones and teeth. Carbamazepine, phenytoin, barbiturates, and chronic alcohol ingestion may shorten the half-life of doxycycline 50% by induction of hepatic enzymes that metabolize the drug.Tetracyclines are excreted mainly in bile and urine. Concentrations in bile exceed those in serum tenfold. Some of the drug excreted in bile is reabsorbed from the intestine (enterohepatic circulation) and may contribute to maintenance of serum levels. 

Ten to fifty percent of various tetracyclines is excreted into the urine, mainly by glom-erular filtration. Ten to forty percent of the drug is excreted in feces. Doxycycline and tigecycline, in contrast to other tetracyclines, are eliminated by nonrenal mechanisms, do not accumulate signifi-cantly, and require no dosage adjustment in renal failure.

Tetracyclines are classified as short-acting (chlortetracycline, tet-racycline, oxytetracycline), intermediate-acting (demeclocycline and methacycline), or long-acting (doxycycline and minocycline) based on serum half-lives of 6–8 hours, 12 hours, and 16–18 hours, respectively. Tigecycline has a half-life of 36 hours. The almost com-plete absorption and slow excretion of doxycycline and minocycline allow for once-daily dosing for certain indications, but by conven-tion these two drugs are usually dosed twice daily.

Clinical Uses

A tetracycline is the drug of choice in the treatment of infections caused by rickettsiae. Tetracyclines are also excellent drugs for the treatment of Mycoplasma pneumonia, chlamydiae, and somespirochetes. They are used in combination regimens to treat gastric and duodenal ulcer disease caused by Helicobacter pylori. They may be used in various gram-positive and gram-negative bacterial infec-tions, including vibrio infections, provided the organism is not resistant. In cholera, tetracyclines rapidly stop the shedding of vibrios, but tetracycline resistance has appeared during epidemics. Tetracyclines remain effective in most chlamydial infections, including sexually transmitted infections. Tetracyclines are no lon-ger recommended for treatment of gonococcal disease because of resistance. A tetracycline—in combination with other antibiot-ics—is indicated for plague, tularemia, and brucellosis. Tetracyclines are sometimes used in the treatment or prophylaxis of protozoal infections, eg, those due to Plasmodium falciparum . Other uses include treatment of acne, exacerbations of bronchitis, community-acquired pneumonia, Lyme disease, relapsing fever, leptospirosis, and some nontuberculous mycobacte-rial infections (eg, Mycobacterium marinum). Tetracyclines formerly were used for a variety of common infections, including bacterial gastroenteritis and urinary tract infections. However, many strains of bacteria causing these infections are now resistant, and other agents have largely supplanted tetracyclines.Minocycline, 200 mg orally daily for 5 days, can eradicate themeningococcal carrier state, but because of side effects and resis-tance of many meningococcal strains, rifampin is preferred. Demeclocycline inhibits the action of antidiuretic hormone inthe renal tubule and has been used in the treatment of inappropri-ate secretion of antidiuretic hormone or similar peptides by cer-tain tumors .

Tigecycline, the first glycylcycline to reach clinical practice,has several unique features that warrant its consideration apart from the older tetracyclines. Many tetracycline-resistant strains are susceptible to tigecycline because the common resistance determi-nants have no activity against it. Its spectrum is very broad. Coagulase-negative staphylococci and Staphylococcus aureus, including methicillin-resistant, vancomycin-intermediate, and vancomycin-resistant strains; streptococci, penicillin-susceptible and resistant; enterococci, including vancomycin-resistant strains; gram-positive rods; Enterobacteriaceae; multidrug-resistant strains of Acinetobacter sp; anaerobes, both gram-positive and gram-negative; rickettsiae, Chlamydia sp, and Legionella pneumophila; and rapidly growing mycobacteria all are susceptible. Proteus sp and P aeruginosa, however, are intrinsically resistant.

Tigecycline, formulated for intravenous administration only, is given as a 100-mg loading dose, then 50 mg every 12 hours. As with all tetracyclines, tissue and intracellular penetration is excellent; consequently, the volume of distribution is quite large and peak serum concentrations are low. Elimination is primarily biliary, and no dosage adjustment is needed for patients with renal insufficiency. In addition to the tetracycline class effects, the chief adverse effect of tigecycline is nausea, which occurs in up to one third of patients, and occasionally vomiting. Neither nausea nor vomiting usually requires discontinuation of the drug.

Tigecycline is Food and Drug Administration (FDA)-approved for treatment of skin and skin-structure infection, intra-abdominal infections, and community-acquired pneumonia. Because active drug concentrations in the urine are relatively low, tigecycline may not be effective for urinary tract infections and has no indica-tion for this use. Because it is active against a wide variety of multidrug-resistant nosocomial pathogens (eg, methicillin-resistant S aureus, extended-spectrum β-lactamase-producing gram-negatives, and Acinetobacter sp, tigecycline is a welcome addition to the antimicrobial drug group. However, its clinical efficacy in infections with multidrug-resistant organisms, com-pared with other agents, is largely unknown.

A. Oral Dosage

The oral dosage for rapidly excreted tetracyclines, equivalent to tetracycline hydrochloride, is 0.25–0.5 g four times daily for adults and 20–40 mg/kg/d for children (8 years of age and older). For severe systemic infections, the higher dosage is indicated, at least for the first few days. The daily dose is 600 mg for demeclo-cycline or methacycline, 100 mg once or twice daily for doxycy-cline, and 100 mg twice daily for minocycline. Doxycycline is the oral tetracycline of choice because it can be given twice daily, and its absorption is not significantly affected by food. All tetracyclines chelate with metals, and none should be orally administered withmilk, antacids, or ferrous sulfate. To avoid deposition in growing bones or teeth, tetracyclines should be avoided in pregnant women and children younger than 8 years.

B. Parenteral Dosage

Several tetracyclines are available for intravenous injection in doses of 0.1–0.5 g every 6–12 hours (similar to oral doses) but doxycy-cline is the usual preferred agent, at a dosage of 100 mg every 12–24 hours. Intramuscular injection is not recommended because of pain and inflammation at the injection site.

Adverse Reactions

Hypersensitivity reactions (drug fever, skin rashes) to tetracyclines are uncommon. Most adverse effects are due to direct toxicity of the drug or to alteration of microbial flora.

A. Gastrointestinal Adverse Effects

Nausea, vomiting, and diarrhea are the most common reasons for discontinuing tetracycline medication. These effects are attribut-able to direct local irritation of the intestinal tract. Nausea, anorexia, and diarrhea can usually be controlled by administering the drug with food or carboxymethylcellulose, reducing drug dos-age, or discontinuing the drug.

Tetracyclines alter the normal gastrointestinal flora, with sup-pression of susceptible coliform organisms and overgrowth of pseudomonas, proteus, staphylococci, resistant coliforms, clostridia, and candida. This can result in intestinal functional disturbances, anal pruritus, vaginal or oral candidiasis, or Clostridium difficile-associated colitis.

B. Bony Structures and Teeth

Tetracyclines are readily bound to calcium deposited in newly formed bone or teeth in young children. When a tetracycline is given during pregnancy, it can be deposited in the fetal teeth, leading to fluorescence, discoloration, and enamel dysplasia; it can also be deposited in bone, where it may cause deformity or growth inhibition. Because of these effects, tetracyclines are generally avoided in pregnancy. If the drug is given for long periods to children younger than 8 years, similar changes can result.

C. Other Toxicities

Tetracyclines can impair hepatic function, especially during pregnancy, in patients with preexisting hepatic insufficiency and when high doses are given intravenously. Hepatic necrosis has been reported with daily doses of 4 g or more intravenously.

Renal tubular acidosis and other renal injury resulting in nitrogen retention have been attributed to the administration of outdated tetracycline preparations. Tetracyclines given along with diuretics may produce nitrogen retention. Tetracyclines other than doxycycline may accumulate to toxic levels in patients with impaired kidney function.Intravenous injection can lead to venous thrombosis. Intramuscular injection produces painful local irritation and should be avoided.

Systemically administered tetracycline, especially demeclocy-cline, can induce sensitivity to sunlight or ultraviolet light, par-ticularly in fair-skinned persons.

Dizziness, vertigo, nausea, and vomiting have been noted par-ticularly with doxycycline at doses above 100 mg. With dosages of 200–400 mg/d of minocycline, 35–70% of patients will have these reactions.